5-Substituted 7,9-difluoro-5H-chromeno[3,4-f]quinoline compounds as selective progesterone receptor modulator compounds

ABSTRACT

The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by progesterone receptor. Also provided are methods of making such compounds and pharmaceutical compositions.

RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Application Ser. No. 60/417,968 filed Oct. 11, 2002, the entire disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates to 5-substituted 7,9-difluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline compounds that may be highly potent receptor- and tissue-selective modulators (i.e. agonists, partial agonists and antagonists) of progesterone receptors and to methods for the making and use of such compounds.

BACKGROUND OF THE INVENTION

[0003] Progesterone receptor (PR) modulators have been widely used in regulation of female reproduction systems and in treatment of female hormone dependent diseases. The effectiveness of known steroidal PR modulators is often tempered by their undesired side-effect profile, particularly during long-term administration. For example, the effectiveness of synthetic progestins as female birth control agents or hormone replacement therapies must be weighed against the increased risk of breast cancer due to progestins' proliferative activity in breast tissue. Similarly, the progesterone antagonist, mifepristone (RU486), if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a glucocorticoid receptor (GR) antagonist. Accordingly, identification of compounds that have good receptor-selectivity for PR over other steroid hormone receptors as well as good tissue-selectivity (e.g. selectivity for uterine tissue over breast tissue) would be of significant value in the improvement of women's health.

[0004] A group of nonsteroidal molecules which contain a di- or tetra-hydroquinoline ring as core pharmacophore (U.S. Pat. Nos. 5,693,646; 5,693,647 and U.S. Pat. No. 5,696,127; PCT Int. Publication Nos. WO 99/41256 A1 and WO 99/41257 A1) have been described as steroid hormone receptor modulator compounds.

[0005] The entire disclosures of the patents, publications and references referred to herein are incorporated by reference herein and are not admitted to be prior art.

SUMMARY OF THE INVENTION

[0006] The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by Progesterone Receptor. More particularly, the invention relates to 5-substituted 7,9-difluoro-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline compounds and compositions which may be high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and/or antagonists for progesterone receptors. Also provided are methods of making such compounds and pharmaceutical compositions. Compounds of the present invention may be represented by the formulae:

[0007] wherein:

[0008] R⁸ is selected from the group of C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ heteroalkenyl, C₂-C₁₂ haloalkenyl, C₂-C₁₂ alkynyl, C₂-C₁₂ heteroalkynyl, C₂-C₁₂ haloalkynyl, aryl and heteroaryl, wherein said alkyl, heteroalkyl, haloalkyl, alkenyl, heteroalkenyl, haloalkenyl, heteroalkynyl, haloalkynyl, alkynyl, aryl and heteroaryl radicals are optionally substituted;

[0009] R⁹ is selected from the group of hydrogen, F, Cl, Br, I, CN, C₁-C₈ alkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ haloalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₂-C₈ haloalkynyl, aryl and heteroaryl, wherein said alkyl, heteroalkyl, haloalkyl, alkenyl, heteroalkenyl, haloalkenyl, heteroalkynyl, haloalkynyl, alkynyl, aryl and heteroaryl radicals are optionally substituted;

[0010] and pharmaceutically acceptable salts and prodrugs thereof.

DEFINITIONS AND NOMENCLATURE

[0011] As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. Furthermore, in an effort to maintain consistency in the naming of compounds of similar structure but differing substituents, the compounds described herein are named according to the following general guidelines. The numbering system for the location of substituents on such compounds is also provided.

[0012] A 5H-chromeno[3,4-f]quinoline is defined by the following structure.

[0013] The term “alkyl,” alone or in combination, refers to an optionally substituted straight-chain or branched-chain or cyclic alkyl radical typically having from 1 to about 12 carbon atoms. The term also includes substituted straight-chain or branched-chain alkyl radicals having from 1 to about 6 carbon atoms as well as those having from 1 to about 4 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.

[0014] The term “alkenyl,” alone or in combination, refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 18 carbon atoms. The term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon double bonds and typically having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, 1,3-butadienyl and the like.

[0015] “Allyl” alone or in combination refers to —CH₂—CH═CH₂.

[0016] “Methylidene” alone or in combination refers to ═CH₂.

[0017] The term “alkynyl,” alone or in combination, refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and typically having from 2 to about 12 carbon atoms. The term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon triple bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl and the like.

[0018] The term “heteroalkyl,” “heteroalkenyl” and “heteroalkynyl” refer to alkyl, alkenyl and alkynyl radicals, as described above, in which one or more skeletal atoms are heteroatoms such as, for example, oxygen, nitrogen, sulfur or combinations thereof. The terms heteroalkyl, heteroalkenyl and heteroalkynyl include radicals in which 1 to about 6 skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof, as well as those in which 1 to 4 skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof and those in which 1 to 2 skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof.

[0019] The term “aryl,” alone or in combination, refers to an optionally substituted aromatic ring system. The term aryl includes monocyclic aromatic rings, polyaromatic rings and polycyclic aromatic ring systems containing from to six about twenty carbon atoms. The term aryl also includes monocyclic aromatic rings, polyaromatic rings and polycyclic ring systems containing from six to about 12 carbon atoms, as well as those containing from 6 to about 10 carbon atoms. The polyaromatic and polycyclic aromatic rings systems may contain from two to four rings. Examples of aryl radicals include, without limitation, phenyl, biphenyl, naphthyl and anthryl ring systems.

[0020] The term “heteroaryl” refers to an optionally substituted aromatic ring system containing from about five to about 20 skeletal ring atoms and having one or more heteroatoms such as, for example, oxygen, nitrogen and sulfur. The term heteroaryl also includes optionally substituted aromatic ring systems having from 5 to about 12 skeletal ring atoms, as well as those having from 5 to about 10 skeletal ring atoms. The term heteroaryl may include five- or six-membered heterocyclic rings, polycyclic heteroaromatic ring systems and polyheteroaromatic ring systems where the ring system has two, three or four rings. The terms heterocyclic, polycyclic heteroaromatic and polyheteroaromatic include ring systems containing optionally substituted heteroaromatic rings having more than one heteroatom as described above (e.g., a six membered ring with two nitrogens), including polyheterocyclic ring systems of from two to four rings. The term heteroaryl includes ring systems such as, for example, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N-alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, benzothiophenyl, purinyl, indolizinyl, thienyl and the like.

[0021] The terms haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include alkyl, alkenyl, and alkynyl structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.

[0022] The terms cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl include optionally substituted cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl radicals.

[0023] The term “carbocycle” includes optionally substituted, saturated or unsaturated, three- to eight-membered cyclic structures in which all of the skeletal atoms are carbon.

[0024] The term “heterocycle” includes optionally substituted, saturated or unsaturated, three- to eight-membered cyclic structures in which one or more skeletal atoms is oxygen, nitrogen, sulfur, or combinations thereof.

[0025] The term “acyl” includes alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituents attached to a compound via a carbonyl functionality (e.g., —CO-alkyl, —CO-aryl, —CO-arylalkyl or —CO-heteroarylalkyl, etc.).

[0026] The term “halogen” includes F, Cl, Br and I.

[0027] The term “mediate” means affect or influence, frequently indirectly or via some intervening action. Thus, for example, conditions mediated by a progesterone receptor are those in which a progesterone receptor plays a role. Progesterone receptors are known to play a role in conditions including, for example, infertility, contraception, pregnancy maintenance and termination, female hormone deficiency, female sexual dysfunction, dysfunctional uterine bleeding, endometriosis, mood disorder, osteoporosis, and hormone-dependent cancers.

[0028] The term “receptor-selectivity” refers to the conditions where a compound displays modulating activity towards one or more particular receptors (e.g., a progesterone receptors) while displaying substantially less or no cross-reactivity towards one or more different receptors (e.g., glucocorticoid receptors). Thus, for example, selective compounds of the present invention may display modulating activity towards progesterone receptors without displaying substantial cross-reactivity towards another steroid hormone receptors. Compounds may be selective for a single receptor, group of similar receptors or multiple receptors.

[0029] The term “tissue-selectivity” refers to compounds that display substantial modulating activity in one tissue (e.g., uterine tissue) while displaying lesser modulating activity in at least one other tissue (e.g., breast tissue). Thus, for example, tissue-selective compounds of the present invention may display substantial modulating activity in uterine and vaginal tissues with lesser modulating activity (partial agonistic or partial antagonistic) in breast tissues relative to the activities of the marketed steroidal progestins in all of the target tissues.

[0030] The term “modulate” means affect or influence, for example, the amount, degree or proportion. Thus, compounds that “modulate” a receptor affect the activity, either positively or negatively, of that receptor. The term may be used to refer to the activity of compounds of a receptor as, for example, an agonist, partial agonist or antagonist. The term also may be used to refer to the effect that a compound has on a physical and/or physiological condition of an individual. For example, certain compounds of the present invention may be used to modulate fertility in an individual. That is, certain compounds of this invention may be used to increase the fertility of an individual, while other compounds of this invention may be used to decrease the fertility of an individual.

[0031] A compound that binds to a receptor and mimics the effect of the native or endogenous ligand is referred to as an “agonist,” while a compound that binds to a receptor and inhibits or has an effect that is opposite that of the native or endogenous ligand is called an “antagonist.” “Partial agonists” give an effect of the same type as the native or endogenous ligand, but of a lower magnitude, while “partial antagonists” are incompletely inhibitory or opposite that of the native or endogenous ligand.

DETAILED DESCRIPTION OF THE INVENTION

[0032] Compounds of the present invention may be represented by the formulae:

[0033] wherein:

[0034] R⁸ is selected from the group of C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ heteroalkenyl, C₂-C₁₂ haloalkenyl, C₂-C₁₂ alkynyl, C₂-C₁₂ heteroalkynyl, C₂-C₁₂ haloalkynyl, aryl and heteroaryl, optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹;

[0035] R⁹ is selected from the group of hydrogen, F, Cl, Br, I, CN, C₁-C₈ alkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkenyl or cycloalkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ haloalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₂-C₈ haloalkynyl, aryl and heteroaryl optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹; and

[0036] R¹⁰ and R¹¹ each independently is hydrogen or C₁-C₄ alkyl; and

[0037] pharmaceutically acceptable salts and prodrugs thereof.

[0038] In one embodiment, R⁸ is selected from the group of:

[0039] R¹ and R² each independently is selected from the group of hydrogen, F, Cl, Br and C₁-C₄ alkyl;

[0040] R³ through R⁵ each independently is selected from the group of hydrogen, F, Cl and C₁-C₄ alkyl; R⁶ is selected from the group of hydrogen, F, Cl, Br, C₁-C₄ alkyl, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹;

[0041] R⁷ is hydrogen, F, or Cl;

[0042] R¹⁰ and R¹¹ each independently is hydrogen or C₁-C₄ alkyl;

[0043] n is 0 or 1;

[0044] X is CH or N; and

[0045] Y is selected from the group of O, S, and NR¹⁰;

[0046]  and pharmaceutically acceptable salts and prodrugs thereof.

[0047] In another embodiment, R⁶ is selected from the group of F, Me, Et, OMe, OEt, SMe, and NMe₂.

[0048] In another embodiment, R⁹ is selected from the group of:

[0049] R⁶ is selected from the group of hydrogen, F, Cl, Br, C₁-C₄ alkyl, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹;

[0050] X is CH or N; and

[0051] R⁷ is hydrogen, F, or Cl; and

[0052] Y is selected from the group of O, S, and NR¹⁰.

[0053] In another embodiment, R⁹ is

[0054] R⁶ is selected from the group of hydrogen, F, Cl, Br, C₁-C₄ alkyl, OR¹⁰, SR¹⁰, and NR¹⁰R¹¹;

[0055] R⁷ is hydrogen, F, or Cl; and

[0056] X is CH or N.

[0057] In the following table, the inventors contemplate any combination of the following Markush groups and those described above for the various variables. TABLE A Table of Markush Groups by Variable Markush Group A Markush Group B Markush Group C Markush Group D R₁ H, F, Cl, Br and F, Cl, Br and C₁-C₂ F, Cl, Br and F and Cl C₁-C₄ alkyl alkyl methyl R₂ H, F, Cl, Br and F, Cl, Br and C₁-C₂ F, Cl, Br and F and Cl C₁-C₄ alkyl alkyl methyl R₃ H, F, Cl, and C₁-C₄ F, Cl and C₁-C₂ F, Cl and methyl F and Cl alkyl alkyl R₄ H, F, Cl, and C₁-C₄ F, Cl and C₁-C₂ F, Cl and methyl F and Cl alkyl alkyl R₅ H, F, Cl, and C₁-C₄ F, Cl and C₁-C₂ F, Cl and methyl F and Cl alkyl alkyl R₆ H, F, Cl, Br, C₁-C₄ H, F, Cl, C₁-C₄ F, Me, Et, OMe, F and methyl alkyl, OR¹⁰, SR¹⁰, alkyl, OMe, OEt, OEt, SMe, and and NR¹⁰R¹¹ NHMe, and NMe₂ NMe₂ R₇ H, F, and Cl F and Cl F R₈ C₁-C₁₂ alkyl, C₁- C₁-C₈ alkyl, C₁-C₈ aryl and heteroaryl, C₁-C₄ alkyl, C₁-C₄ C₁₂ heteroalkyl, heteroalkyl, C₁-C₈ optionally heteroalkyl, C₁-C₄ C₁-C₁₂ haloalkyl, haloalkyl, C₂-C₈ substituted with haloalkyl, C₂-C₄ C₂-C₁₂ alkenyl, alkenyl, C₂-C₈ one or more of H, alkenyl, C₂-C₄ C₂-C₁₂ heteroalkenyl, C₂- C₁-C₄ alkyl, F, Cl, heteroalkenyl, C₂- heteroalkenyl, C₂- C₈ haloalkenyl, C₂- Br, CN, NH₂, C₄ haloalkenyl, C₂- C₁₂ haloalkenyl, C₈ alkynyl, C₂-C₈ NHCH₃, N(CH₃)₂, C₄ alkynyl, C₂-C₄ C₂-C₁₂ alkynyl, heteroalkynyl, C₂- SH, SCH₃, OH, heteroalkynyl, and C₂-C₁₂ C₈ haloalkynyl, OCH₃, OCF₃, CF₃, C₂-C₄ haloalkynyl heteroalkynyl, C₂- aryl and heteroaryl, C(O)CH₃, OR¹⁰, C₁₂ haloalkynyl, optionally SR¹⁰ and NR¹⁰R¹¹ aryl and heteroaryl, substituted with optionally one or more substituted with substituents one or more independently substituents selected from the independently group of H, C₁-C₄ selected from the alkyl, F, Cl, Br, I, group of H, C₁-C₄ CN, NO₂, NH₂, alkyl, F, Cl, Br, I, NHCH₃, N(CH₃)₂, CN, NO₂, NH₂, SH, SCH₃, OH, NHCH₃, N(CH₃)₂, OCH₃, OCF₃, CF₃, SH, SCH₃, OH, C(O)CH₃, CO₂CH₃, OCH₃, OCF₃, CF₃, C(O)NH₂, OR¹⁰, C(O)CH₃, CO₂CH₃, SR¹⁰ and NR¹⁰R¹¹ C(O)NH₂, OR¹⁰, SR¹⁰ and NR¹⁰R¹¹ R₉ H, F, Cl, Br, I, CN, aryl and heteroaryl, H, Br, Cl, C₁-C₄ C₁-C₈ alkyl, C₁-C₈ optionally alkyl, C₁-C₄ heteroalkyl, C₁-C₈ substituted with heteroalkyl, C₁-C₄ haloalkyl, C₂-C₈ one or more haloalkyl, C₂-C₄ alkenyl or substituents alkenyl, C₂-C₄ cycloalkenyl, C₂- independently heteroalkenyl, C₂- C₈ heteroalkenyl, selected from H, C₄ haloalkenyl, C₂- C₂-C₈ haloalkenyl, C₁-C₄ alkyl, F, Cl, C₄ alkynyl and C₂- C₂-C₈ alkynyl, C₂- Br, CN, NH₂, C₄ heteroalkynyl, C₈ heteroalkynyl, NHCH₃, N(CH₃)₂, C₂-C₄ haloalkynyl C₂-C₈ haloalkynyl, SH, SCH₃, OH, aryl and heteroaryl, OCH₃, OCF₃, optionally OR¹⁰, SR¹⁰, and substituted with NR¹⁰R¹¹ one or more substituents independently selected from H, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰R¹¹ R₁₀ H and C₁-C₄ alkyl H and methyl H R₁₁ H and C₁-C₄ alkyl H and methyl H n 0 or 1 X CH or N N Y O, S, and NR¹⁰ O and S S

[0058] In one aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a progesterone receptor modulator compound of formulae I or II shown above wherein R¹ through R¹¹, n, X, Y, have the same definitions as given above.

[0059] In a further aspect, the present invention comprises a method of modulating a process mediated by progesterone receptors comprising administering to a patient having a condition mediated by progesterone receptors an effective amount of a compound of the formulae I or II shown above, wherein R¹ through R¹¹, n, X, Y, have the same definitions as those given above.

[0060] Any of the compounds of the present invention can be synthesized as pharmaceutically acceptable salts for incorporation into various pharmaceutical compositions. As used herein, pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic, succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydroxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art.

[0061] PR agonist, partial agonist and antagonist compounds of the present invention may be particularly useful for female hormone replacement therapy and as modulators of fertility (e.g., as contraceptives, contragestational agents or abortifacients, in vitro fertilization, pregnancy maintenance), either alone or in conjunction with one or more estrogen receptor modulators. PR modulator compounds of this invention also may be used in the treatment of dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas (uterine fibroids), hot flushes, mood disorders, and meningiomas. The PR modulator compounds of this invention also may be used in the treatment of various hormone-dependent cancers, including, without limitation, cancers of ovaries, breast, endometrium and prostate. PR modulator compounds of this invention can also be used in treatment of female osteoporosis, either alone or in combination with one or more estrogen receptor modulators.

[0062] It will be understood by those skilled in the art that while the compounds of the present invention will typically be employed as selective agonists, partial agonists or antagonists, that there may be instances where a compound with a mixed steroid receptor profile is preferred. For example, use of a PR agonist (i.e., progestin) in female contraception often leads to the undesired effects of increased water retention and acne flare ups. In this instance, a compound that is primarily a PR agonist, but also displays some AR and MR modulating activities, may prove useful. Specifically, the mixed MR effects would be useful to control water balance in the body, while the AR effects would help to control any acne flare ups that occur.

[0063] Furthermore, it will be understood by those skilled in the art that compounds of the present invention, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, compounds of the present invention can be used in combination with other hormones and other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.

[0064] Representative PR modulator compounds (i.e., agonists, partial agonists and antagonists) according to the present invention include:

[0065] 7,9-difluoro-5(Z)-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 10);

[0066] 7,9-difluoro-5(Z)-(2-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 12);

[0067] 7,9-difluoro-5(Z)-(2-chlorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 13);

[0068] 7,9-difluoro-5(Z)-(4-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 14);

[0069] 7,9-difluoro-5(Z)-(3-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 15);

[0070] 7,9-difluoro-5 (Z)-(4-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 16);

[0071] 7,9-difluoro-5(Z)-(2,5-difluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 17);

[0072] 7,9-difluoro-5 (Z)-(2-methoxybenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 18);

[0073] 7,9-difluoro-5(Z)-(2-methyl-5-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 19);

[0074] 7,9-difluoro-5(Z)-(3-methyl-4-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 20);

[0075] 7,9-difluoro-5 (Z)-(2-methyl-3-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 21);

[0076] 7,9-difluoro-5(Z)-(3-methyl-2-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 22);

[0077] 7,9-difluoro-5(Z)-(2,3-dimethylbenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 23);

[0078] 7,9-difluoro-5(Z)-cyanomethylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 24);

[0079] 7,9-difluoro-5(Z)-hexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 25);

[0080] 7,9-difluoro-5(Z)-(2-methoxy-5-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 26);

[0081] 7,9-difluoro-5(Z)-(2,4,5-trifluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 27);

[0082] 7,9-difluoro-5-methylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 28);

[0083] 7,9-difluoro-5 (Z)-bromomethylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 29);

[0084] 7,9-difluoro-5(Z)-(3-thienylmethylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 30);

[0085] 7,9-difluoro-5(Z)-(2-thienylmethylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 31);

[0086] (±)-7,9-difluoro-5-methoxy-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 32);

[0087] (±)-7,9-difluoro-5-phenyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 33);

[0088] (±)-7,9-difluoro-5-(3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 34);

[0089] (±)-7,9-difluoro-5-(1,3-benzodioxol-5-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 35);

[0090] (±)-7,9-difluoro-5-(4-bromophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 36);

[0091] (±)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 37);

[0092] (−)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 38);

[0093] (+)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 39);

[0094] (±)-7,9-difluoro-5-(3-fluorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 40);

[0095] (±)-7,9-difluoro-5-(3-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 41);

[0096] (±)-7,9-difluoro-5-(3-bromophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 42);

[0097] (±)-7,9-difluoro-5-(4-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 43);

[0098] (±)-7,9-difluoro-1,2-dihydro-2,2,4,5-tetramethyl-5H-chromeno[3,4-f]quinoline (Compound 44);

[0099] (±)-7,9-difluoro-5-(2-oxo-2-phenylethyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 45);

[0100] (±)-7,9-difluoro-5-ethyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 46);

[0101] (±)-7,9-difluoro-5-ethenyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 47);

[0102] (±)-7,9-difluoro-5-(2-oxo-3-butenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 48);

[0103] Methyl (±)-7,9-difluoro-1,2-dihydro-α,α,2,2,4-pentamethyl-5H-chromeno[3,4-f]quinoline-5-ethanoate (Compound 49);

[0104] (±)-7,9-difluoro-5-ethynyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 50);

[0105] (±)-7,9-difluoro-5-cyano-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 51);

[0106] (±)-7,9-difluoro-5-butyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 52);

[0107] (±)-7,9-difluoro-5-(2-thienyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 53);

[0108] (±)-7,9-difluoro-5-(2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 54);

[0109] (±)-7,9-difluoro-5-allyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 55);

[0110] (±)-7,9-difluoro-5-[3-(trifluoromethyl)phenyl]-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 56);

[0111] Ethyl (±)-7,9-difluoro-1,2-dihydro-α-methylene-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline-5-propanoate (Compound 57);

[0112] (±)-7,9-difluoro-1,2-dihydro-β-methylene-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline-5-propanol (Compound 58);

[0113] (±)-7,9-difluoro-1,2-dihydro-β-methylene-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline-5-propanol acetate(Compound 59);

[0114] (±)-7,9-difluoro-5-(1-methylethenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 60);

[0115] (±)-7,9-difluoro-5-(N-methyl-2-pyrrolyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 61);

[0116] 5 (±)-7,9-difluoro-5-phenylethynyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 62);

[0117] (±)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 63);

[0118] (−)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 64);

[0119] (±)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 65);

[0120] (±)-7,9-difluoro-5-(5-methyl-2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 66);

[0121] (±)-7,9-difluoro-5-(2-benzo[b]furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 67);

[0122] (±)-7,9-difluoro-5-[4-(dimethylamino)phenyl]-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 68);

[0123] (±)-7,9-difluoro-5-(5-methyl-2-thienyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 69);

[0124] (±)-7,9-difluoro-5-(5-methoxy-2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 70);

[0125] (±)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 71);

[0126] (−)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 72);

[0127] (+)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 73);

[0128] (±)-7,9-difluoro-5-(1-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 74);

[0129] (−)-7,9-difluoro-5-(1-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 75);

[0130] (+)-7,9-difluoro-5-(1-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 76);

[0131] (±)-7,9-difluoro-5-(4,5-dimethyl-2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 77);

[0132] (±)-7,9-difluoro-5-(2-methyl-1-propenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 78);

[0133] (±)-7,9-difluoro-5-(3,4-dimethyl-2-thienyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 79);

[0134] (±)-7,9-difluoro-5-(3-(3-bromophenyl)phenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 80); and

[0135] 7,9-difluoro-5(Z)-(2-methylbenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 81).

[0136] The sequence of steps for the general schemes to synthesize the compounds of the present invention is shown below. In each of the Schemes the R groups (e.g., R⁸, R⁹, etc.) correspond to the specific substitution patterns noted in the Examples. However, it will be understood by those skilled in the art that other functionalities disclosed herein at the indicated positions of compounds of formulae I and II also comprise potential substituents for the analogous positions on the structures within the Schemes. In a further aspect, the present invention contains a novel process for the preparation of the compounds of the present invention.

[0137] The process of Scheme I begins with addition of organolithium or Grignard reagents to lactones 1 followed by the treatment with a Lewis acid, such as p-toluenesulfonic acid, to produce compounds of structure 2. An alternative route starts with the treatment of lactone 1 with Tebbe reagent to provide compound 4. Bromination with NBS affords the bromomethylidene 5. Palladium catalyzed Suzuki reaction of compound 5 with a boronic acid gives the methylidene derivatives of structure 2.

[0138] Scheme II describes the synthesis of the 5-alkyl/aryl analogues 7. Reduction of lactone 1 with DIBAL-H followed by acid catalyzed methylation provides lactal intermediates 6. Treatment of the lactal 6 with a nucleophile in the presence of a Lewis acid, such as BF₃—OEt₂, affords the final products of structure 7. Alternatively, addition of a nucleophile directly to lactone 1 affords hemiacetals 8, which are treated with silane in the presence of a Lewis acid leading to the same products 7.

[0139] The compounds of the present invention also include racemates, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds. Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral column chromatography.

[0140] As noted above, PR modulator compounds of the present invention can be combined in a mixture with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and particularly in human patients. The particular carrier employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired. Suitable administration routes include enteral (e.g., oral), topical, suppository, inhalable and parenteral (e.g., intravenous, intramuscular and subcutaneous).

[0141] In preparing the compositions in oral liquid dosage forms (e.g., suspensions, elixirs and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be employed. Similarly, when preparing oral solid dosage forms (e.g., powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like will be employed. Due to their ease of administration, tablets and capsules represent a desirable oral dosage form for the pharmaceutical compositions of the present invention.

[0142] For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid in solubility or serve as preservatives, may also be included. Furthermore, injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like will be employed.

[0143] For topical administration, the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as Eucerin™, available from Beiersdorf (Cincinnati, Ohio). Examples of suitable cream bases are Nivea™ Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose Cream™, available from Johnson & Johnson (New Brunswick, N.J.), hydrophilic ointment (USP) and Lubridermn, available from Warner-Lambert (Morris Plains, N.J.).

[0144] The pharmaceutical compositions and compounds of the present invention will generally be administered in the form of a dosage unit (e.g., tablet, capsule, etc.). The compounds of the present invention generally are administered in a daily dosage of from about 1 μg/kg of body weight to about 50 mg/kg of body weight. Typically, the compounds of the present invention are administered in a daily dosage of from about 2 μg/kg to about 25 mg/kg of body weight. Preferably, the compounds of the present invention are administered in a daily dosage of from about 10 μg/kg to about 5 mg/kg body weight. As recognized by those skilled in the art, the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.

[0145] Compounds of this invention also have utility when radio- or isotopically-labeled as ligands for use in assays to determine the presence of PR in a cell background or extract. Such compounds are particularly useful due to their ability to selectively activate progesterone receptors, and can therefore be used to determine the presence of such receptors in the presence of other steroid receptors or related intracellular receptors.

[0146] Compounds and pharmaceutical compositions of the present invention may be extremely potent activators of PR. For example, compounds and compositions of the present invention may display 50% maximal activation of PR at a concentration of less than 50 nM. Some compounds and compositions of the present invention may display 50% maximal activation of PR at a concentration of less than 20 nM, and some may display such activity at a concentration of 10 nM or less. In addition, the compounds of the present invention may be tissue-selective modulators. For example, the compounds of this invention may suppress estrogen-induced endometrial stimulation in uterus equally efficacious as marketed steroidal modulator compounds but display reduced proliferative activity or antagonized endogenous hormone induced proliferative activity in breasts.

[0147] The invention will be further illustrated by reference to the following non-limiting Examples.

EXAMPLE 1

[0148] Preparation of 7,9-difluoro-5(Z)-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 10 Structure 2 of Scheme L where R⁹=phenyl).

[0149] General procedure I for preparing 5(Z)-substituted methylidene compounds (Structure 2 of Scheme I) from lactones (Structure 1 of Scheme I) and a Grignard or organolithium reagent. To a solution (0.2-1.0 M) of lactone 1 in THF was added a freshly prepared Grignard or organolithium solution (3-5 equiv.). The reaction mixture was stirred for 1-12 h until the starting material was consumed and then was poured into ice-cold 50% NH₄Cl and extracted with EtOAc (2×). The extracts were washed with brine (3×), dried (Na₂SO₄) and concentrated. A solution (0.2-0.5 M) of the crude lactol intermediate in CH₂Cl₂ was treated with a catalytic amount of p-toluenesulfonic acid at room temperature for 3 h, quenched with saturated NaHCO₃ and extracted with EtOAc (2×). The extracts were washed with brine (3×), dried (Na₂SO₄), and concentrated. Flash chromatography (silica gel, EtOAc-hexane 2% to 10% gradient) of the crude mixture afforded the final product in good yield. To prevent photoisomerization of the benzylidene analogues, the dehydration step and the work-up should be carried out in a light-controlled environment.

[0150] Compound 10 was prepared from benzyl Grignard and 7,9-difluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 11, structure 1 of Scheme I) according to the general procedure as a yellow solid: ¹H-NMR (400 MHz, CDCl₃) 7.84 (d, J=7.9, 2H), 7.40-7.36 (m, 4H), 7.20-7.14 (m, 1H), 6.76-6.71 (m, 1H), 6.66 (d, J=8.4, 1H), 5.67 (s, 1H), 5.54 (s, 1H), 4.24 (bs, 1H), 2.18 (s, 3H), 1.35 (bs, 6H).

EXAMPLE 2

[0151] Preparation of 7,9-difluoro-5(Z)-(2-fluorobenzylidene)-1,2-dihydro-212,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 12. Structure 2 of Scheme I where R⁹=2 -fluorophenyl).

[0152] This compound was prepared in a similar fashion as that described in Example 1 from 2-fluorobenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I,) as a yellow solid: ¹H-NMR (400 MHz, CDCl₃) 8.44-8.38 (m, 1H), 7.39 (d, J=8.4, 1H), 7.23-7.14 (m, 3H), 7.06-7.00 (m, 1H), 6.76-6.70 (m, 1H), 6.67 (d, J=8.4, 1H), 6.00 (s, 1H), 5.56 (s, 1H), 4.25 (bs, 1H), 2.12 (s, 3H), 1.35 (bs, 6H).

EXAMPLE 3

[0153] Preparation of 7,9-difluoro-5(Z)-(2-chlorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 13. Structure 2 of Scheme L where R⁹=2-chlorophenyl).

[0154] This compound was prepared in a similar fashion as that described in Example 1 from 2-chlorobenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, CDCl₃) 8.45 (d, J=8.0, 1H), 7.39 (d, J=8.5, 1H), 7.36-7.30 (m, 2H), 7.18-7.13 (m, 2H), 6.73-6.70 (m, 1H), 6.69 (d, J=8.5, 1H), 6.25 (s, 1H), 5.56 (s, 1H), 4.27 (bs, 1H), 2.13 (s, 3H), 1.35 (bs, 6H).

EXAMPLE 4

[0155] Preparation of 7,9-difluoro-5(Z)-(4-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 14 Structure 2 of Scheme L, where R⁹=4-pyridyl).

[0156] This compound was prepared in a similar fashion as that described in Example 1 from 4-picolyl lithium and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, CDCl₃) 8.59 (d, J=5.8, 2H), 7.69 (d, J=5.1, 2H), 7.44 (d, J=8.5, 1H), 7.20-7.18 (m, 1H), 6.81-6.79 (m, 1H), 6.73 (d, J=8.5, 1H), 5.63 (s, 1H), 5.58 (s, 1H), 4.31 (bs, 1H), 2.09 (d, J=1.2, 3H), 1.37 (bs, 6H).

EXAMPLE 5

[0157] Preparation of 7,9-difluoro-5(Z)-(3-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 15. Structure 2 of Scheme I, where R⁹=3 -fluorophenyl.

[0158] This compound was prepared in a similar fashion as that described in Example 1 from 3-fluorobenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, Acetone-d₆) 7.82-7.79 (ddd, J=2.0, 2.0, 9.5, 1H), 7.66 (d, J=8.5, 1H), 7.52-7.38 (m, 3H), 7.05-6.97 (m, 2H), 6.87 (d, J=8.5, 1H), 6.10 (bs, 1H), 5.79 (s, 1H), 5.58 (s, 1H), 2.08 (s, 3H), 1.40 (bs, 6H).

EXAMPLE 6

[0159] Preparation of 7,9-difluoro-5(Z)-(4-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 16, Structure 2 of Scheme I, where R⁹=4 -fluorophenyl).

[0160] This compound was prepared in a similar fashion as that described in Example 1 from 4-fluorobenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, Acetone-d₆) 7.92-7.88 (dd, J=5.6, 8.9, 2H), 7.64 (d, J=8.5, 1H), 7.46-7.42 (ddd, J=2.1, 2.1, 9.5, 1H), 7.19-7.14 (dd, J=8.7, 8.7, 2H), 6.98-6.96 (m, 1H), 6.84 (d, J=8.5, 1H), 6.07 (bs, 1H), 5.76 (s, 1H), 5.57 (s, 1H), 2.08 (s, 3H), 1.31 (bs, 6H).

EXAMPLE 7

[0161] Preparation of 7,9-difluoro-5(Z)-(2,5-difluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 17, Structure 2 of Scheme I, where R⁹=2,5-difluorophenyl).

[0162] This compound was prepared in a similar fashion as that described in Example 1 from 2,5-difluorobenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, Acetone-d₆) 8.26-8.21 (m, 1H), 7.69 (d, J=8.5, 1H), 7.51-7.47 (ddd, J=2.4, 2.4, 9.9, 1H), 7.22-7.16 (ddd, J=4.7, 9.3, 9.3, 1H), 7.09-7.00 (m, 2H), 6.90 (d, J=8.4, 1H), 6.16 (bs, 1H), 6.03 (s, 1H), 5.59 (s, 1H), 2.10 (s, 3H), 1.30 (bs, 6H).

EXAMPLE 8

[0163] Preparation of 7,9-difluoro-5(Z)-(2-methoxybenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 18, Structure 2 of Scheme I, where R⁹=2-methoxyphenyl).

[0164] This compound was prepared in a similar fashion as that described in Example 1 from 2-methoxybenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, Acetone-d₆) 8.31-8.28 (dd, J=1.6, 7.8, 1H), 7.61 (d, J=8.5, 1H), 7.44-7.41 (ddd, J=2.0, 2.0, 9.9, 1H), 7.26-7.22 (ddd, J=1.7, 7.5, 7.5, 1H), 7.04-6.90 (m, 3H), 6.82 (d, J=8.5, 1H), 6.26 (s, 1H), 6.12 (bs, 1H), 5.55 (s, 1H), 3.80 (s, 3H), 2.11 (s, 3H), 1.33 (bs, 6H).

EXAMPLE 9

[0165] Preparation of 7,9-difluoro-5(Z)-(2-methyl-5-fluorobenzalidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[34-f]quinoline (Compound 19. Structure 2 of Scheme I, where R⁹=2-methyl-5-fluorophenyl).

[0166] This compound was prepared in a similar fashion as that described in Example 1 from 2-methyl-5-fluorobenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, Acetone-d₆) 8.14-8.11 (dd, J=2.7, 14.2, 1H), 7.66 (d. J=8.5, 1H), 7.46 (ddd, J=2.2, 2.2, 9.9, 1H), 7.24-7.21 (dd, J=6.3, 8.2, 1H), 7.01-6.96 (ddd, J=3.0, 8.6, 10.4, 1H), 6.94-6.90 (ddd, J=2.8, 8.4, 8.4, 1H), 6.88 (d, J=8.5, 1H), 6.12 (s, 1H), 6.03 (s, 1H), 5.59 (s, 1H), 2.27 (s, 3H), 2.12 (s, 3H), 1.34 (bs, 6H).

EXAMPLE 10

[0167] Preparation of 7,9-difluoro-5(Z)-(3-methyl-4-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 20. Structure 2 of Scheme I where R⁹=3-methyl-4-pyridyl).

[0168] This compound was prepared in a similar fashion as that described in Example 1 from 3-methyl-4-picolyl lithium and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (500 MHz, CDCl₃) 8.49 (d, J=4.9, 1H), 8.39 (s, 1H), 8.19 (d, J=5.5, 1H), 7.43 (d, J=8.5, 1H), 7.17 (ddd, J=9.5, 2.4, 2.1, 1H), 6.77 (ddd, J=10.1, 8.5, 3.1, 1H), 6.73 (d, J=8.5, 1H), 5.92 (s, 1H), 5.56 (s, 1H), 4.31 (bs, 1H), 2.24 (s, 3H), 2.12 (d, J=1.2, 3H), 1.38 (bs, 6H).

EXAMPLE 11

[0169] Preparation of 7,9-difluoro-5(Z)-(2-methyl-3-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 21, Structure 2 of Scheme I, where R⁹=2-methyl-3-fluorophenyl).

[0170] This compound was prepared in a similar fashion as that described in Example 1 from 2-methyl-3-fluorobenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, Acetone-d₆) 8.06 (d, J=7.8, 1H), 7.66 (d, J=8.5, 1H), 7.47-7.43 (ddd, J=2.2, 2.2, 9.9, 1H), 7.31-7.26 (dd, J=7.9, 14.0, 1H), 7.01-6.93 (m, 2H), 6.87 (d, J=8.5, 1H), 6.11 (bs, 1H), 6.02 (s, 1H), 5.59 (s, 1H), 2.20 (s, 3H), 2.13 (s, 3H), 1.33 (bs, 6H).

EXAMPLE 12

[0171] Preparation of 7,9-difluoro-5(Z)-(3-methyl-2-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 22. Structure 2 of Scheme I where R⁹=3-methyl-2-pyridyl).

[0172] This compound was prepared in a similar fashion as that described in Example 1 from 3-methyl-2-picolyl lithium and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (500 MHz, CDCl₃) 8.50 (dd, J=4.6, 1.5, 1H), 7.50 (dd, J=7.6, 1.5, 1H), 7.40 (d, J=8.5, 1H), 7.15-7.12 (m, 1H), 7.07 (dd, J=7.6, 4.6, 1H), 6.69 (d, J=8.5, 1H), 6.66 (ddd, J=10.2, 8.2, 2.7, 1H), 6.01 (s, 1H), 5.53 (d, J=1.2, 1H), 4.26 (bs, 1H), 2.38 (s, 3H), 2.26 (d, J=1.2, 3H), 1.33 (bs, 6H).

EXAMPLE 13

[0173] Preparation of 7,9-difluoro-5(Z)-(2,3-dimethylbenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 23 Structure 2 of Scheme I where R⁹=2,3-dimethylphenyl).

[0174] This compound was prepared in a similar fashion as that described in Example 1 from 2,3-dimethylbenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, Acetone-d₆) 7.97 (d, J=7.7, 1H), 7.63 (d, J=8.5, 1H), 7.44-7.41 (ddd, J=2.2, 2.2, 10.1, 1H), 7.16-7.13 (dd, J=7.6, 7.6, 1H), 7.07 (d, J=7.3, 1H), 6.94-6.89 (ddd, J=2.9, 8.9, 11.0, 1H), 6.84 (d, J=8.5, 1H), 6.07 (bs, 1H), 6.05 (s, 1H), 5.70 (s, 1H), 2.28 (s, 3H), 2.14 (s, 3H), 2.06 (s, 3H), 1.30 (bs, 6H).

EXAMPLE 14

[0175] Preparation of 7,9-difluoro-5(Z)-cyanomethylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 24 Structure 2 of Scheme I, where R⁹=cyano).

[0176] This compound was prepared in a similar fashion as that described in Example 1 from acetonitrile lithium and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 7.50 (d, J=8.6, 1H), 7.24-7.19 (m, 1H), 6.87-6.81 (m, 1H), 6.83 (d, J=8.6, 1H), 5.58 (s, 1H), 4.76 (s, 1H), 4.40 (s, 1H), 2.11 (d, J=1.2, 3H), 1.57 (bs, 6H).

EXAMPLE 15

[0177] Preparation of 7,9-difluoro-5(Z)-hexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 25 Structure 2 of Scheme I, where R⁹=pentyl).

[0178] This compound was prepared in a similar fashion as that described in Example 1 from n-hexyl lithium and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (500 MHz, CDCl₃) 7.32 (d, J=8.2, 1H), 7.10 (ddd, J=9.8, 2.7, 1.8, 1H), 6.69 (ddd, J=10.4, 8.5, 2.7, 1H), 6.59 (d, J=8.5, 1H), 5.49 (s, 1H), 4.86 (t, J=7.9, 1H), 4.15 (bs, 1H), 2.35-2.27 (m, 2H), 2.08 (d, J=1.2, 3H), 1.74-1.64 (m, 4H), 1.63-1.58 (m, 1H), 1.36-1.25 (m, 8H), 1.20-1.13 (m, 4H), 1.00-1.93 (m, 2H).

EXAMPLE 16

[0179] Preparation of 7,9-difluoro-5(Z)-(2-methoxy-5-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 26 Structure 2 of Scheme I, where R⁹=2-methoxy-5-fluorophenyl).

[0180] This compound was prepared in a similar fashion as that described in Example 1 from 2-methoxy-5-fluorobenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, Acetone-d₆) 8.15-8.12 (ddd, J=1.6, 1.6, 10.6, 1H), 7.63 (d, J=8.5, 1H), 7.46-7.43 (ddd, J=2.2, 2.2, 10.2, 1H), 7.00-6.95 (m, 3H), 6.86-6.84 (d, J=8.4, 1H), 6.27 (s, 1H), 6.06 (bs, 1H), 5.56 (s, 1H), 3.81 (s, 3H), 2.09 (s, 3H), 1.19 (bs, 6H).

EXAMPLE 17

[0181] Preparation of 7,9-difluoro-5(Z)-(2,4,5-trifluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 27 Structure 2 of Scheme I, where R⁹=2,4,5-trifluorophenyl).

[0182] This compound was prepared in a similar fashion as that described in Example 1 from 2,4,5-trifluorobenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (500 MHz, CDCl₃) 8.38-8.32 (m, 1H), 7.41 (d, J=8.2, 1H), 7.18-7.16 (m, 1H), 6.93-6.87 (m, 1H), 6.79-6.75 (m, 1H), 6.69 (d, J=8.2, 1H), 5.88 (s, 1H), 5.56 (s, 1H), 4.28 (bs, 1H), 2.08 (s, 3H), 1.34 (bs, 6H).

EXAMPLE 18

[0183] Preparation of 7,9-difluoro-5-methylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 28. Structure 4 of Scheme I).

[0184] Treatment of Compound 11 (Structure 1 of Scheme I, where R⁶=methyl) with Tebbe reagent (0.5 M in toluene) afforded compound 28 as a yellow solid: ¹H-NMR (500 MHz, CDCl₃) 7.35 (d, J=8.2, 1H), 7.13 (ddd, J=9.8, 2.4, 2.1, 1H), 6.71 (ddd, J=10.1, 8.5, 2.8, 1H), 6.65 (d, J=8.2, 1H), 5.51 (d, J=0.9, 1H), 5.19 (d, J=1.5, 1H), 4.52 (d, J=1.5, 1H), 4.20 (bs, 1H), 2.14 (d, J=1.2, 3H), 1.30 (bs, 6H).

EXAMPLE 19

[0185] Preparation of 7,9-difluoro-5(Z)-bromomethylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 29, Structure S of Scheme I).

[0186] Treatment of Compound 28 (Structure 4 of Scheme I) with NBS in DMF at rt for 10 min and standard work-up followed by chromatography provided compound 29 as a yellow foam: ¹H-NMR (500 MHz, CDCl₃) 7.38 (d, J=8.2, 1H), 7.15-7.11 (m, 1H), 6.75 (ddd, J=10.1, 8.2, 2.7, 1H), 6.67 (d, J=8.2, 1H), 5.54 (s, 1H), 5.53 (s, 1H), 4.24 (bs, 1H), 2.08 (d, J=1.5, 3H), 1.30 (bs, 6H).

EXAMPLE 20

[0187] Preparation of 7,9-difluoro-5(Z)-(3-thienylmethylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 30, Structure 2 of Scheme I, R⁹=3-thiophene).

[0188] To a solution of compound 29 (Structure 5 of Scheme I) in DME was added Pd(PPh₃)₄ (3 mol %) and the mixture was stirred at rt for 15 min. A solution of 3-thiopheneboronic acid in DME and CsF were added to the reaction mixture. The reaction was heated at 80° C. for 2 h, quenched with NaHCO₃ (sat'd aqueous) and extracted with EtOAc. Removal of solvent and chromatography of the crude mixture afforded 30 as yellow foam: ¹H-NMR (500 MHz, CDCl₃) 7.77 (d, J=2.4, 1H), 7.54 (d, J=4.0, 1H), 7.37 (d, J=8.2, 1H), 7.32 (dd, J=4.9, 3.1, 1H), 7.17-7.13 (m, 1H), 6.76-6.72 (m, 1H), 6.65 (d, J=8.2, 1H), 5.76 (s, 1H), 5.54 (s, 1H), 4.23 (bs, 1H), 2.09 (d, J=0.9, 3H), 1.34 (bs, 6H).

EXAMPLE 21

[0189] Preparation of 7,9-difluoro-5(Z)-(2-thienylmethylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 31 Structure 2 of Scheme I R⁹=2-thiophene).

[0190] This compound was prepared in a similar fashion as that described in Example 20 from compound 29 (Structure 5 of Scheme I) and 2-thiopheneboronic acid as yellow foam: ¹H-NMR (500 MHz, CDCl₃) 7.39 (d, J=8.5, 1H), 7.33 (d, J=4.9, 1H), 7.23 (d, J=3.7, 1H), 7.16-7.13 (m, 1H), 7.05 (dd, J=5.2, 3.7, 1H), 6.78-6.74 (m, 1H), 6.65 (d, J=8.2, 1H), 5.99 (s, 1H), 5.56 (s, 1H), 4.25 (bs, 1H), 2.09 (d, J=0.9, 3H), 1.36 (bs, 6H).

EXAMPLE 22

[0191] Preparation of (±)-7,9-difluoro-5-methoxy-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 32 Structure 6 of Scheme II).

[0192] Reduction of Compound 11 (Structure 1 of Scheme II) with DIBAL-H in toluene at −78° C. for 1 h provided a lactal intermediate, which, upon treatment with TsOH in methanol, afforded Compound 32 as a white solid: ¹H NMR (500 MHz, CDCl₃) 7.39 (d, J=8.6, 1H), 7.21 (dt, J=8.8, 2.4, 1H), 6.75 (td, J=9.3, 2.7, 1H), 6.60(d, J=8.2, 1H), 6.40 (s, 1H), 5.53 (d, J=1.5, 1H), 4.04 (s, 1H), 3.49 (s, 3H), 2.27 (d, J=1.2, 3H), 1.34 (s, 3H), 1.20 (s, 3H).

EXAMPLE 23

[0193] Preparation of (±)-7,9-difluoro-5-phenyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 33. Structure 7 of Scheme II, where R⁸=phenyl).

[0194] This compound was prepared by the following general procedure:

[0195] To a stirred solution of bromobenzene in THF at −78° C. under nitrogen atmosphere was added n-BuLi in hexanes (1.6 M). After one hour a solution of compound 11 (structure 1 of Scheme II) in THF was added dropwise and after 2 hours at −78° C. the temperature was allowed to rise to −55° C. The reaction mixture was stirred for an additional hour at this temperature, poured into an aqueous ammonium chloride solution and extracted twice with ethyl acetate. The organic extracts were washed with brine, combined, dried (Na₂SO₄), concentrated and purified using column chromatography on silica gel (heptanes/ethyl acetate: gradient 20/1 to 10/1) to give structure 8 of Scheme II (R⁸=Phenyl) as an oil. This oil was dissolved in dichloromethane, and 0.2 mL of triethylsilane and 0.17 mL of boron trifluoride diethyl etherate were added. After stirring for 6 hours a saturated solution of sodium hydrogencarbonate was added and extracted three times with dichloromethane. The organic extracts were combined, dried (Na₂SO₄) and concentrated. Purification using HPLC (LUNA C18(2), CH₃CN/water, gradient 6/4 to 10/0) yielded compound 33 as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.70 (d, J=8.8, 1H), 7.40 (dq, J=10, 1.8, 1H), 7.30 (M, 5H), 7.10 (s, 1H), 6.93 (d, J=8.8, 1H), 6.92 (M, 1H), 6.54 (d, J=1.6, 1H), 5.52 (t, J=1.6, 1H), 2.30 (d, J=1.2, 3H), 1.30 (s, 3H), 1.27 (s, 3H).

EXAMPLE 24

[0196] Preparation of (±)-7,9-difluoro-5-(3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 34, Structure 7 of Scheme II, where R⁸=3-methylbenzene).

[0197] Compound 34 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and 3-bromotoluene as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.85 (d, J=8.6, 1H), 7.56 (dq, J=10, 1.8, 1H), 7.37 (t, J=7.6, 1H), 7.30 (s, 1H), 7.25 (d, J=7.8, 1H), 7.23 (s, 1H), 7.21 (d, J=8, 1H), 7.09 (d, J=8.8, 1H), 7.09 (M, 1H), 6.70 (s, 1H), 5.69 (t, J=1.6, 1H), 2.41 (s, 3H), 2.21 (s, 3H), 1.46 (s, 3H), 1.44 (s, 3H).

EXAMPLE 25

[0198] Preparation of (±)-7,9-difluoro-5-(1,3-benzodioxol-5-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 35, Structure 7 of Scheme II, where R⁸=5-(1,3-benzodioxole)).

[0199] Compound 35 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and 5-bromo[1,3]benzodioxole as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.85 (d, J=8.6, 1H), 7.75 (dq, J=10, 1.8, 1H), 7.16 (s, 1H), 7.10 (m, 1H), 7.08 d, J=8.8, 1H), 7.04 (d, J=1.6, 1H), 6.96 (d, J=8.8, 1H), 6.8 (dd, J=8.2, 1.8, 1H), 6.69 (d, J=1.8, 1H), 6.21 (s, 2H), 5.68 (t, J=1.6, 1H), 2.22 (s, 3H), 1.45 (s, 3H), 1.42 (s, 3H).

EXAMPLE 26

[0200] Preparation of (±)-7,9-difluoro-5-(4-bromophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 36, Structure 7 of Scheme II, where R⁸=4-bromobenzene).

[0201] Compound 36 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and 1,4-dibromobenzene as a solid: ¹H NMR (500 MHz, CDCl₃) 7.38 (d, J=8.4, 1H), 7.33 (m, 2H), 7.1 (m, 2H), 6.99 (dq, J=9.6, 2, 1H), 6.91 (s, 1H), 6.69 (d, J=8.8, 1H), 6.56 (m, 1H), 5.48 (s, 1H), 4.06 (s, 1H), 1.97 (s, 1H), 1.30 (s, 3H), 1.26 (s, 3H).

EXAMPLE 27

[0202] Preparation of (±)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 37, Structure 7 of Scheme II, Where, R⁸=4-chloro-3-methylbenzene).

[0203] Compound 37 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and 5-bromo-2-chlorotoluene as a solid: ¹H NMR (500 MHz CDCl₃) 7.38 (d, J=8.4, 1H), 7.15 (d, 8.8, 1H), 7.09 (d, J=2, 1H), 6.98 (m, 2H), 6.90 (s, 1H), 6.70 (d, J=8.8, 1H), 6.57 (m, 1H), 5.49 (s, 1H), 4.06 (s, 1H), 2.24 (s, 1H), 1.98 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H).

EXAMPLE 28

[0204] Preparation of (−)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline and (+)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compounds 38 and 39, Structure 7 of Scheme II, where R⁸=4-chloro-3-methylbenzene).

[0205] These compounds were isolated as enantiomers of Compound 37 by a chiral HPLC separation. Retention times: OJ column 0.46 cm×25 cm, flow 1 ml/min, heptanes/ethanol 85/15; Rt=12 min and 15 min. Compound 38 is the (−)-isomer: ¹H NMR (500 MHz CDCl₃) 7.38 (d, J=8.4, 1H), 7.15 (d, 8.8, 1H), 7.09 (d, J=2, 1H), 6.98 (m, 2H), 6.90 (s, 1H), 6.70 (d, J=8.8, 1H), 6.57 (m, 1H), 5.49 (s, 1H), 4.06 (s, 1H), 2.24 (s, 1H), 1.98 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H); Compound 39 is the (+)-isomer: ¹H NMR (500 MHz CDCl₃) 7.38 (d, J=8.4, 1H), 7.15 (d, 8.8, 1H), 7.09 (d, J=2, 1H), 6.98 (m, 2H), 6.90 (s, 1H), 6.70 (d, J=8.8, 1H), 6.57 (m, 1H), 5.49 (s, 1H), 4.06 (s, 1H), 2.24 (s, 1H), 1.98 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H).

EXAMPLE 29

[0206] Preparation of (±)-7,9-difluoro-5-(3-fluorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 40, Structure 7 of Scheme II, where R⁸=3-fluorobenzene).

[0207] Compound 40 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and 3-bromofluorobenzene as a solid: ¹H NMR (500 MHz, CDCl₃) 7.38 (d, J=8.4, 1H), 7.18 (m, 1H), 7.05 (d, J=8.2, 1H), 7.0 (dq, J=10, 2, 1H), 6.95 (s, 1H), 6.89 (m, 2H), 6.70 (d, J=8.6, 1H), 6.57 (m, 1H), 5.49 (d, J=1.4, 1H), 4.06 (s, 1H), 1.99 (s, 3H), 1.31 (s, 3H), 1.27 (s, 3H).

EXAMPLE 30

[0208] Preparation of (±)-7,9-difluoro-5-(3-chlorophenyl)-112-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 41, Structure 7 of Scheme II, where R⁸=3-chlorobenzene).

[0209] Compound 41 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and 3-bromochlorobenzene as a solid: ¹H NMR (500 MHz, DMSO-d,) 7.59 (d, J=8.8, 1H), 7.36 (dq, J=10.4, 1.8, 1H), 7.31 (m, 2H), 7.14 (s, 1H), 7.10 (m, 1H), 7.0 (s, 1H), 6.96 (m, 1H), 6.79 (d, J=8.8, 1H), 6.57 (d, J=2, 1H), 5.44 (t, J=1.6, 1H), 1.90 (d, J=1.4, 3H), 1.22 (s, 3H), 1.19 (s, 3H).

EXAMPLE 31

[0210] Preparation of (±)-7,9-difluoro-5-(3-bromophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 42. Structure 7 of Scheme II, where R⁸=3-bromobenzene).

[0211] Compound 42 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and 1,3-dibromobenzene as a solid: ¹H NMR (600 MHz, DMF-d₆) 7.88 (d, J=8.7, 1H), 7.67 (d, J=8.4, 1H), 7.61 (s, 1H), 7.59 (dq, J=10.2, 2.1, 1H), 7.50 (t, J=7.8, 1H), 7.46 (d, J=7.8, 1H), 7.30 (s, 1H), 7.13 (m, 1H), 7.11 (d, J=8.7, 1H), 6.77 (s, 1H), 5.72 (s, 1H), 2.22 (s, 3H), 1.47 (s, 3H), 1.44 (s, 3H).

EXAMPLE 32

[0212] Preparation of (±)-7,9-difluoro-5-(4-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 43. Structure 7 of Scheme II, where R⁸=4-chlorobenzene).

[0213] Compound 43 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and 4-bromochlorobenzene as a solid: ¹H NMR (500 MHz, CDCl₃) 7.38 (d, J=8.4, 1H), 7.17 (M, 4H), 6.99 (dq, J=9.6, 2, 1H), 6.92 (s, 1H), 6.69 (d, J=8.6, 1H), 6.56 (m, 1H), 5.48 (s, 1H), 4.45 (s, 1H), 1.97 (s, 3H), 1.30 (s, 3H), 1.25 (s, 3H).

EXAMPLE 33

[0214] Preparation of (±)-7,9-difluoro-1,2-dihydro-2,2,4,5-tetramethyl-5H-chromeno[3,4-f]quinoline (Compound 44 Structure 7 of Scheme II where R⁸=methyl).

[0215] Compound 44 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and methyllithium as a solid: ¹H NMR (500 MHz, DMF-d₇) 7.54 (d, J=8.8, 1H), 7.41 (dq, J=10, 2, 1H), 7.02 (m, 1H), 6.74 (d, J=8.8, 1H), 6.36 (s, 1H), 6.16 (q, J=6.4, 1H), 5.50 (m, 1H), 2.23 (s, 3H), 1.32 (d, J=6.6, 3H), 1.21 (s, 3H), 1.16 (s, 3H).

EXAMPLE 34

[0216] Preparation of (±)-7,9-difluoro-5-(2-oxo-2-Ihenylethyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 45, Structure 7 of Scheme II, where R⁸=2-oxo-2-phenylethyl).

[0217] To a stirred solution of 0.31 mmol of compound 32 (Structure 6 of Scheme II) in 10 mL of dichloromethane and 0.3 mL of 1-phenyl-1-trimethylsilyloxyethene at −78° C. under a nitrogen atmosphere was added 0.22 mL of boron trifluoride diethyl etherate. After stirring for 30 minutes a saturated aqueous solution of sodium hydrogencarbonate was added and the resulting mixture was extracted three times with dichloromethane. The organic extracts were combined, dried (Na₂SO₄) and concentrated. Purification using column chromatography on silica gel (toluene) and then HPLC (LUNA C18(2), CH₃CN/water, gradient 95/5 to 100/0) yielded 50 mg of compound 45 as a solid: ¹H NMR (500 MHz, DMF-d₇) 7.91 (dd, J=8.8, 1.2, 2H), 7.64 (d, J=8.6, 1H), 7.64 (tt, J=7.4, 1H), 7.50 (d, J=8.4, 1H), 7.49 (m, 2H), 6.95 (m, 1H), 6.80 (dd, 1H), 6.82 (d, J=8.4, 1H), 6.46 (d, J=2, 1H), 5.55 (t, J=1.8, 1H), 3.92 (dd, J=17.4, 10, 1H), 3.02, (dd, J=17.4, 2.4, 1H), 2.31, (s, 3H), 1.27 (s, 3H), 1.17 (s, 3H).

EXAMPLE 35

[0218] Preparation of (±)-7,9-difluoro-5-ethyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 46, Structure 7 of Scheme II where R⁸=ethyl).

[0219] Hydrogenation at atmospheric pressure of compound 47 in ethyl acetate using PtO₂ as catalyst and purification using HPLC (LUNA C 18(2), CH₃CN/water) yielded compound 46 as a solid: ¹H NMR (500 MHz, DMF-d₇) 7.57 (d, J=8.4, 1H), 7.43 (dq, J=10.2, 1.8, 1H), 7.05 (m, 1H), 6.77 (d, J=8.6, 1H), 6.39 (d, J=1.6, 1H), 5.87 (dd, J=10.2, 3.6, 1H), 5.54 (t, J=1.8, 1H), 2.25 (d, J=1.4, 3H), 1.74 (m, 1H), 1.52 (m, 1H), 1.27 (s, 3H), 1.18 (s, 3H), 1.00 (t, J=7.4, 3H).

EXAMPLE 36

[0220] Preparation of (±)-7,9-difluoro-5-ethenyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 47. Structure 7 of Scheme II, where R⁸=vinyl).

[0221] Compound 47 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and tributyl(ethenyl)tin as a solid: ¹H NMR (600 MHz, DMF-d₇) 7.78 (d, J=8.7, 1H), 7.59 (dt, J=10.2, 1H), 7.21 (m, 1H), 7.11 (d, J=8.4, 1H), 6.67 (m, 1H), 6.61 (s, 1H), 6.23 (m, 1H), 5.72 (s, 1H), 5.45 (dt, J=10.8, 1H), 5.15 (dt, J=17.7, 1H), 2.41 (s, 3H), 1.43 (s, 6H).

EXAMPLE 37

[0222] Preparation of (±)-7,9-difluoro-5-(2-oxo-3-butenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 48. Structure 7 of Scheme II where R⁸=2-oxo-3-butenyl).

[0223] Compound 48 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 2-trimethylsilyloxy-1,3-butadiene as a solid. ¹H NMR (600 MHz, DMF-d₇) 7.61 (d, J=8.7, 1H), 7.47 (dt, J=10.5, 2.4, 1H), 7.02 (m, 1H), 6.80 (d, J=8.7, 1H), 6.64 (dd, J=10.5, 2.7, 1H), 6.45 (s, 1H), 6.40 (dd, J=17.7, 11.1, 1H), 6.16 (d, J=18, 1H), 5.91 (d, J=11.4, 1H), 5.55 (s, 1H), 3.48 (dd, 1H), 2.62 (dd, J=17.1, 2.7, 1H), 2.29 (s, 3H), 1.26 (s, 3H), 1.18 (s, 3H).

EXAMPLE 38

[0224] Preparation of Methyl (±)-7,9-difluoro-1,2-dihydro-α, α, 2,2,4-pentamethyl-5H-chromeno[3,4-f]quinoline-5-ethanoate (Compound 49. Structure 7 of Scheme II where R⁸=1-methoxycarbonyl-1-methylethyl).

[0225] Compound 49 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 1-methoxy-2-methyl-1-trimethylsilyloxypropene as a solid: ¹H NMR (600 MHz, DMF-d₇) 7.86 (d, J=8.7, 1H), 7.64 (dt, J=5.3, 1.8, 1H), 7.21 (m, 1H), 7.04 (d, J=8.4, 1H), 6.80 (s, 1H), 6.48 (s, 1H), 5.73 (s, 1H), 3.81 (s, 3H), 2.49 (s, 3H), 1.57 (s, 3H), 1.31 (s, 3H), 1.28 (s, 3H), 1.10 (s, 3H).

EXAMPLE 39

[0226] Preparation of (±)-7,9-difluoro-5-ethynyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 50, Structure 7 of Scheme II where R⁸=acetylene).

[0227] Compound 50 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and ethynyltributyltin as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.77 (d, J=8.6, 1H), 7.66 (dt, J=10, 1.6, 1H), 7.29 (m, 1H), 7.00 (d, J=8.4, 1H), 6.86 (d, J=2.2, 1H), 6.70 (s, 1H), 5.74 (s, 1H), 3.81 (dd, J=2.4, 0.8, 1H), 2.59 (s, 3H), 1.49 (s, 3H), 1.37 (s, 3H).

EXAMPLE 40

[0228] Preparation of (±)-7,9-difluoro-5-cyano-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 51, Structure 7 of Scheme II where R=cyano).

[0229] Compound 51 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and trimethylsilyl cyanide as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.56 (d, J=8.8, 1H), 7.46 (dq, J=10, 1.8, 1H), 7.1 (m, 1H), 7.04 (s, 1H), 6.79 (d, J=8.8, 1H), 6.64 (s, 1H), 5.50 (q, 1H), 2.26 (s, 3H), 1.20 (s, 3H), 1.06 (s, 3H).

EXAMPLE 41

[0230] Preparation of (±)-7,9-difluoro-5-butyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 52. Structure 7 of Scheme II, where R⁸=butyl).

[0231] Compound 52 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and n-butyllithium as a solid: ¹H NMR (600 MHz, DMF-d₇) 7.60 (d, J=7.1, 1H), 7.46 (d, J=7.1, 1H), 7.08 (m, 1H), 6.80 (d, J=5.7, 1H), 6.42 (s, 1H), 5.98 (d, J=7.1, 1H), 5.57 (s, 1H), 2.28 (s, 3H), 1.78 (m, 1H), 1.48 (m, 3H), 1.3 (m, 2H), 1.3 (s, 3H), 1.20 (s, 3H), 0.86 (t, J=4.2, 3H).

EXAMPLE 42

[0232] Preparation of (±)-7,9-difluoro-5-(2-thienyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 53. Structure 7 of Scheme II where R⁸=2-thiophene.

[0233] Compound 53 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 2-(tributylstannyl)thiophene as a solid: ¹H NMR (600 MHz, DMF-d₇)7.80 (d, J=8.7, 1H), 7.53 (dd, J=5.4, 1.2, 1H), 7.43 (d, J=10.2, 1H), 7.26 (s, 1H), 6.96 (m, 1H), 6.93 (m, 1H), 6.91 (d, J=8.7, 1H), 6.78 (d, J=3.6, 1H), 6.52 (s, 1H), 5.57 (s, 1H), 2.14 (s, 3H), 1.27 (s, 6H).

EXAMPLE 43

[0234] Preparation of (±)-7,9-difluoro-5-(2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 54, Structure 7 of Scheme II, where R⁸=2-furyl).

[0235] Compound 54 was prepared in a similar fashion as that described in Example 23 from Compound 32 (Structure 6 of Scheme II) and 2-(tributylstannyl)furan as a solid: ¹H NMR (600 MHz, DMF-d₇) 7.69 (s, 1H), 7.65 (d, J=8.7, 1H), 7.44 (dt, J=11.4, 1H), 6.99 (s, 1H), 6.94 (m, 1H), 6.88 (d, 8.4, 1H), 6.48 (s, 1H), 6.30 (q, J=1.5, 1H), 5.92 (d, J=3.3, 1H), 5.49 (s, 1H), 2.10 (s, 3H), 1.26 (s, 3H), 1.21 (s, 3H).

EXAMPLE 44

[0236] Preparation of (±)-7,9-difluoro-5-allyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 55, Structure 7 of Scheme II, where R⁸=allyl).

[0237] Compound 55 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and allyltrimethylsilane as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.78 (d, J=8.6, 1H), 7.64, (dq, J=10.2, 1.8, 1H), 7.24 (m, 1H), 6.97 (d, J=8.6, 1H), 6.61 (d, J=1.6, 1H), 6.24 (dd, J=10, 4, 1H), 6.09 (m, 1H), 6.73 (t, J=1.6, 1H), 5.27 (m, 1H), 5.23 (m, 1H), 2.71 (m, 1H), 2.48 (m, 1H), 2.44 (s, 3H), 1.46 (s, 3H), 1.38 (s, 3H).

EXAMPLE 45

[0238] Preparation of (±)-7,9-difluoro-5-[3-(trifluoromethyl)phenyl]-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 56. Structure 7 of Scheme II, where R⁸=3-trifluoromethylphenyl).

[0239] Compound 56 was prepared in a similar fashion as that described in Example 23 from Compound 11 (Structure 1 of Scheme II) and 3-bromobenzotrifluoride as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.87 (d, J=8.6, 1H), 7.84 (m, 1H), 7.78 (t, J=7.6, 2H), 7.72 (m, 1H), 7.57 (dq, J=10, 1.8, 1H), 7.38 (s, 1H), 7.12 (m, 1H), 7.11 (d, J=8.6, 1H), 6.78 (d, J=2, 1H), 6.71 (t, J=1.6, 1H), 2.21 (d, J=1.4, 3H), 1.45 (s, 3H), 1.44 (s, 3H).

EXAMPLE 46

[0240] Preparation of Ethyl (±)-7,9-difluoro-1,2-dihydro-α-methylene-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline-5-propanoate (Compound 57. Structure 7 of Scheme II, where R⁸=2-ethoxycarbonyl-2-propenyl).

[0241] Compound 57 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and ethyl 2-(trimethylsilylmethyl)acrylate as a solid: ¹H NMR (600 MHz, DMF-d₇) 7.52 (d, J=8.7, 1H), 7.38 (dq, J=10.2, 1.8, 1H), 6.94 (m, 1H), 6.69 (d, J=8.4, 1H), 6.35 (d, J=1.5, 1H), 6.17 (dd, J=10.5, 4.2, 1H), 6.12 (d, J=1.2, 1H), 5.45 (s, 1H), 5.40 (s, 1H), 4.12 (m, 2H), 2.57 (dd, J=15, 10.5, 1H), 2.44 (dd, J=15, 3.9, 1H), 2.23 (s, 3H), 1.21 (s, 3H), 1.18, (t, J=7.2, 3H), 1.06 (s, 3H).

EXAMPLE 47

[0242] Preparation of (±)-7,9-difluoro-1,2-dihydro-(3-methylene-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline-5-propanol (Compound 58, Structure 7 of Scheme II, where R⁸=2-hydroxymethyl-2-propenyl).

[0243] To a solution of 64 mg of compound 59 (Structure 7 of Scheme II, where R⁸=2-acetyloxymethyl-2-propenyl) in 2 mL of methanol, 0.5 mL of THF and 0.5 mL of aqueous 20% KOH stirred at room temperature for 3 hours 2 M hydrochloric acid was added to adjust the pH to 7. A saturated solution of sodium hydrogencarbonate was added and the resulting mixture was extracted with ethyl acetate. The organic extract was dried (Na₂SO₄) and concentrated to yield 60 mg of compound 58 as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.46 (dd, J=8.6, 1.8, 1H), 7.32 (dq, J=10, 1.8, 1H), 6.90 (m, 1H), 6.65 (dd, J=8.4, 1.8, 1H), 6.11 (d, J=10.6, 1H), 5.40 (s, 1H), 4.98 (s, 1H), 4.66 (s, 1H), 4.20 (d, J=14.2, 1H), 3.90 (d, J=14.2, 1H), 2.36 (dd, J=15.6, 10.8, 1H), 2.17 (s, 3.5H), 2.13 (s, 0.5H), 1.14 (s, 3H), 1.05 (s, 3H).

EXAMPLE 48

[0244] Preparation of (±)-7,9-difluoro-1,2-dihydro-β-methylene-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline-5-propanol acetate(Compound 59. Structure 7 of Scheme II, where R⁸=2-acetyloxymethyl-2-propenyl).

[0245] Compound 59 was prepared by a similar procedure as described in Example 34 from Compound 32 (Structure 6 of Scheme II) and ethyl 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate as a solid: ¹H NMR (600 MHz, DMF-d₇) 7.63 (d, J=8.7, 1H), 7.49 (d, J=9.9, 1H), 7.07 (m, 1H), 6.82 (d, J=8.7, 1H), 6.45 (s, 1H), 6.26 (dd, J=10.8, 2.7, 1H), 5.58 (s, 1H), 5.23 (s, 1H), 5.05 (s, 1H), 4.71 (d, J=13.5, 1H), 4.60 (d, J=13.5, 1H), 2.63 (dd, J=16.2, 11.1, 1H), 2.35 (s, 1H), 2.32 (s, 3H), 2.08 (s, 3H), 1.29 (s, 3H), 1.22 (s, 3H).

EXAMPLE 49

[0246] Preparation of (±)-7,9-difluoro-5-(1-methylethenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 60. Structure 7 of Scheme II, where R⁸=1-methylvinyl).

[0247] Compound 60 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and (propen-2-yl)tributyltin as a solid: ¹H NMR (600 MHz, DMF-d₇) 7.76 (d, J=8.3, 1H), 7.57 (dq, J=10.2, 1.8, 1H), 7.21 (m, 1H), 7.02 (d, J=8.7, 1H), 6.58 (s, 1H), 6.44 (s, 1H), 5.60 (m, 1H), 5.23 (s, 1H), 4.63 (s, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H).

EXAMPLE 50

[0248] Preparation of (±)-7,9-difluoro-5-(N-methyl-2-pyrrolyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 61. Structure 7 of Scheme II where R⁸=N-methyl-2-pyrrolyl).

[0249] Compound 61 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and N-methyl-2-(tributylstannyl)pyrrole as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.65 (dd, J=8.6, 2, 1H), 7.43 (m, 1H), 7.05 (s, 1H), 6.92 (m, 1H), 6.89 (m, 1H), 6.81 (m, 1H), 6.43 (s, 1H), 5.74 (m, 1H), 5.48 (m, 1H), 5.42 (m, 1H), 3.95 (m, 3H), 1.98 (d, J=2, 3H), 1.29 (d, J=2.2, 3H), 1.21 (d, 3H).

EXAMPLE 51

[0250] Preparation of (±)-7,9-difluoro-5-phenylethynyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 62. Structure 7 of Scheme II where R⁸=phenylacetylene).

[0251] Compound 62 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and (phenylethynyl)tributyltin as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.64 (dd, J=8.6, 1H), 7.52 (m, 1H), 7.37 (m, 3H), 7.28 (m, 2H), 7.14 (m, 1H), 6.92 (d, J=3, 1H), 6.86 (m, 1H), 6.76 (s, 1H), 5.60 (s, 1H), 2.49 (d, J=1.8, 3H), 1.35 (d, J=2, 3H), 1.22 (d, J=2.2, 3H).

EXAMPLE 52

[0252] Preparation of (±)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 63. Structure 7 of Scheme II, where R⁸=2-benzo[b]thiophene).

[0253] Compound 63 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 2-(tributylstannyl)benzo[b]thiophene as a solid: ¹H NMR (600 MHz, DMF-d₇) 8.11 (m, 1H), 7.94 (m, 1H), 7.89 (d, J=8.7, 1H), 7.61 (dq, J=9.9, 1H), 7.51 (m, 3H), 7.20 (s, 1H), 7.12 (m, 1H), 7.12 (d, J=8.4, 1H), 6.75 (d, J=1.5, 1H), 5.72 (s, 1H), 2.36 (d, J=1.2, 3H), 1.48 (s, 3H), 1.45 (s, 3H).

EXAMPLE 53

[0254] Preparation of (−)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[34-f]quinoline and (+)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 64 and 65, Structure 7 of Scheme II where R⁸=2-benzo[b]thiophene).

[0255] Compounds 64 and 65 were prepared by chiral HPLC separation of Compound 63 (Structure 7 of Scheme II, where R⁸=2-benzothiophene) as pure enantiomers. Retention times: (R,R) Whelk-O2 10/100; 0.46 cm×25 cm, flow 1 ml/min, heptanes/iso-propanol 98/2; Rt=14 min and 18 min. Compound 64 is the (−)-isomer; and compound 65 is the (+)-isomer.

EXAMPLE 54

[0256] Preparation of (±)-7,9-difluoro-5-(5-methyl-2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 66, Structure 7 of Scheme II, where R⁸=5-methyl-2-furyl).

[0257] Compound 66 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 5-methyl-2-(tributylstannyl)furan as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.82 (m, 1H), 7.62 (m, 1H), 7.12 (m, 2H), 7.05 (m, 1H), 6.65 (s, 1H), 6.07 (s, 1H), 5.92 (m, 1H), 5.67 (s, 1H), 2.41 (dd, J=8.4, 3H), 2.22 (d, J=8, 3H), 1.44 (m, 3H), 1.39 (m, 3H).

EXAMPLE 55

[0258] Preparation of (±)-7,9-difluoro-5-(2-benzo[b]furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 67, Structure 7 of Scheme II where R⁸=2-benzo[b]furyl).

[0259] Compound 67 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 2-(tributylstannyl)benzo[b]furan as a solid: ¹H NMR (400 MHz, CDCl₃) 7.49 (d, J=8.6, 1H), 7.40 (d, J=8.6, 1H), 7.36 (d, J=8.4, 1H), 7.26 (m, 1H), 7.14 (m, 1H), 7.08 (m, 2H), 6.71 (d, J=8.4, 1H), 6.58 (m, 1H), 6.23 (s, 1H), 5.48 (d, J=1.4, 1H), 4.05 (s, 1H), 2.04 (s, 3H), 1.30 (s, 3H), 1.25 (s, 3H).

EXAMPLE 56

[0260] Preparation of (±)-7,9-difluoro-5-[4-(dimethylamino)phenyl]-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 68. Structure 7 of Scheme II where R⁸=4-dimethylaminophenyl).

[0261] Compound 68 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and (3-[dimethylamino]phenyl)tributyltin as a solid: ¹H NMR (400 MHz, DMSO-d₆) 7.54 (d, J=8.8, 1H), 7.32 (dq, J=10.2, 1H), 6.92 (m, 2H), 6.88 (m, 1H), 6.85 (s, 1H), 6.74 (d, J=8.6, 1H), 6.54 (m, 2H), 6.43 (d, J=1.8, 1H), 5.38 (s, 1H), 2.82 (s, 6H), 1.90 (s, 3H), 1.20 (s, 3H), 1.16 (s, 3H).

EXAMPLE 57

[0262] Preparation of (±)-7,9-difluoro-5-(5-methyl-2-thienyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 69, Structure 7 of Scheme II, where R⁸=5-methyl-2-thiophene).

[0263] Compound 69 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 5-methyl-2-(tributylstannyl)thiophene as a solid: ¹H NMR (400 MHz, DMSO-d₆) 7.55 (d, J=8.6, 1H), 7.36 (dq, J=10.2, 1.8, 1H), 7.05 (s, 1H), 6.96 (m, 1H), 6.75 (d, J=3.4, 1H), 6.52 (dd, J=3.8, 1.2, 1H), 6.48 (d, J=2, 1H), 6.40 (d, J=3.4, 1H), 5.41 (s, 1H), 2.11 (s, 3H), 2.01 (s, 3H), 1.18 (s, 3H), 1.17 (s, 3H).

EXAMPLE 58

[0264] Preparation of (±)-7,9-difluoro-5-(5-methoxy-2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 70. Structure 7 of Scheme II, where R⁸=5-methoxy-2-furyl.

[0265] Compound 70 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 5-methoxy-2-(tributylstannyl)furan as a solid: ¹H NMR (600 MHz, CDCl₃) 7.35 (d, J=8.7, 1H), 7.06 (dt, J=9.6, 1H), 6.80 (s, 1H), 6.65 (d, J=8.4, 1H), 6.62 (m, 1H), 5.69 (d, J=3.3, 1H), 5.47 (s, 1H), 4.88 (d, J=3.3, 1H), 3.98 (s, 1H), 3.79 (s, 3H), 2.05 (d, J=0.9, 3H), 1.29 (s, 3H), 1.22 (s, 3H).

EXAMPLE 59

[0266] Preparation of (±)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 71, Structure 7 of Scheme II, where R⁸=2-propynyl).

[0267] Compound 71 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 2-propynyltributyltin as a solid: ¹H NMR (400 MHz, DMF-d₇) 7.57 (d, J=8.8, 1H), 7.43 (dq, J=10.4, 1.8, 1H), 7.05 (m, 1H), 6.77 (d, J=8.6, 1H), 6.44 (s, 1H), 6.19 (q, J=4.6, 1H), 5.51 (t, J=1.8, 1H), 2.84 (t, J=2.8, 1H), 2.64 (m, 1H), 2.48 (dq, J=17.6, 2.8, 1H), 2.27 (s, 3H), 1.25 (s, 3H), 1.16 (s, 3H).

EXAMPLE 60

[0268] Preparation of (−)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline and (+)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compounds 72 and 73, Structure 7 of Scheme II, where R⁸=2-propynyl).

[0269] Compounds 72 and 73 were prepared by chiral HPLC separation of Compound 71 (Structure 7 of Scheme II, where R⁸=2-propynyl) as pure enantiomers. Retention times: OJ column 2.0 cm×50 cm, flow 10 ml/min, heptanes/ethanol 90/10; Rt=40 min and 45 min. Compound 72 is the (−)-isomer; and Compound 73 is the (+)-isomer.

EXAMPLE 61

[0270] Preparation of (±)-7,9-difluoro-5-(1-propynyl)-,1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 74, Structure 7 of Scheme II where R⁸═I-propynyl).

[0271] Compound 74 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and (1-propynyl)tributyltin as a solid: ¹H NMR (400 MHz, DMSO-d₆) 7.46 (d, J=8.6, 1H), 7.42 (dq, J=10, 1.8, 1H), 7.08 (m, 1H), 6.67 (d, J=8.6, 1H), 6.54 (q, J=2.2, 1H), 6.48 (d, J=2, 1H), 5.46 (t, J=1.6, 1H), 2.29 (s, 3H), 1.69 (d, J=2, 3H), 1.25 (s, 3H), 1.11 (s, 3H).

EXAMPLE 62

[0272] Preparation of (−)-7,9-difluoro-5-(1-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline and (+)-7,9-difluoro-5-(1-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compounds 75 and 76. Structure 7 of Scheme II, where R⁸=1-propynyl.

[0273] Compounds 75 and 76 were prepared by chiral HPLC separation of Compound 74 (Structure 7 of Scheme II, where R⁸=1-propynyl) as pure enantiomers. Retention times: OJ column 2.0 cm×50 cm, flow 10 ml/min, heptanes/ethanol 90/10; Rt=37 min and 47 min. Compound 75 is the (−)-isomer; and Compound 76 is the (+)-isomer.

EXAMPLE 63

[0274] Preparation of (±)-7,9-difluoro-5-(4,5-dimethyl-2-furyl)-1,2-dihydro-212,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 77, Structure 7 of Scheme II where R⁸=4,5-dimethyl-2-furyl).

[0275] Compound 77 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 2,3-dimethyl-5-(tributylstannyl)furan as a solid: ¹H NMR (400 MHz, DMSO-d₆) 7.54 (d, J=8.6, 1H), 7.39 (dq, J=10, 1.8, 1H), 6.97 (m, 1H), 6.80 (s, 1H), 6.74 (d, J=8.4, 1H), 6.46 (d, J=1.8, 1H), 5.55 (s, 1H), 5.40 (s, 1H), 2.12 (s, 3H), 1.92 (s, 3H), 1.69 (s, 3H), 1.21 (s, 3H), 1.13 (s, 3H).

EXAMPLE 64

[0276] Preparation of (±)-7,9-difluoro-5-(2-methyl-1-propenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 78. Structure 7 of Scheme II, where R⁸=2-methyl-1-propenyl).

[0277] Compound 78 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 2-methylpropenylmagnesium bromide as a solid: ¹H NMR (400 MHz, DMSO-d₆) 7.47 (d, J=8.6, 1H), 7.36 (m, 1H), 6.98 (m, 1H), 6.66 (d, J=8.4, 1H), 6.41 (d, J=1.8, 1H), 6.38 (d, J=7.4, 1H), 5.42 (s, 1H), 5.17 (d, J=7.6, 1H), 2.11 (s, 3H), 1.88 (s, 3H), 1.62 (s, 3H), 1.21 (s, 3H), 1.14 (s, 3H).

EXAMPLE 65

[0278] Preparation of (±)-7,9-difluoro-5-(3,4-dimethyl-2-thiennyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 79. Structure 7 of Scheme II, where R⁸=3,4-dimethyl-2-thiophene).

[0279] Compound 79 was prepared in a similar fashion as that described in Example 34 from Compound 32 (Structure 6 of Scheme II) and 3,4-dimethyl-2-(tributylstannyl)thiophene as a solid: ¹H NMR (600 MHz, DMSO-d₆) 7.55 (d, J=9, 1H), 7.38 (m, 1H), 7.12 (s, 1H), 6.91 (m, 1H), 6.87 (s, 1H), 6.76 (d, J=8.4, 1H), 6.46 (d, J=1.8, 1H), 5.38 (s, 1H), 2.27 (s, 3H), 2.05 (s, 3H), 1.93 (s, 3H), 1.18 (s, 3H), 1.16 (s, 3H).

EXAMPLE 66

[0280] Preparation of (±)-7,9-difluoro-5-(3-(3-bromophenyl)phenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 80. Structure 7 of Scheme II, where R⁸=3-(3-bromophenyl)phenyl).

[0281] Compound 80 was isolated as aminor product of the reaction described in example 31 as a solid: ¹H NMR (600 MHz, DMSO-d₆) 7.65 (t, J=2.1, 1H), 7.58 (d, J=8.7, 1H), 7.55 (m, 1H), 7.49 (m, 1H), 7.41 (t, J=8.4, 1H), 7.35 (m, 2H), 7.09 (d, J=7.8, 1H), 7.08 (s, 1H), 6.93 (m, 1H), 6.79 (d, J=8.7, 1H), 6.53 (d, J=2.1, 1H), 5.45 (s, 1H), 1.97 (s, 3H), 1.21 (s, 6H).

EXAMPLE 67

[0282] Preparation of 7,9-difluoro-5(Z)-(2-methylbenzylidene)-1,2-dihydro-212,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 81. Structure 2 of Scheme I, where R⁹=2-methylphenyl).

[0283] This compound was prepared in a similar fashion as that described in Example 1 from 2-methylbenzyl Grignard reagent and Compound 11 (Structure 1 of Scheme I) as a yellow solid: ¹H-NMR (400 MHz, CDCl₃) 8.30 (d, J=8.0, 1H), 7.38 (d, J=8.4, 1H), 7.31-7.24 (m, 1H), 7.17-7.10 (m, 4H), 6.73-6.82 (m, 1H), 6.66 (d, J=8.4, 1H), 5.96 (s, 1H), 5.53 (s, 1H), 4.24 (s, 1H), 2.28 (s, 3H), 2.14 (s, 3H), and 1.25 (bs, 6H).

EXAMPLE 68

[0284] The PR modulating activities and binding affinities of selected steroid receptor modulator compounds of the present invention were evaluated utilizing the cotransfection assay, and the standard receptor competitive binding assays, according to the following illustrative Examples. The receptor-selectivities of the selected analogues towards PR relative to other steroid hormone receptors were also assessed in the cotransfection assay under the same cell background. The potential tissue-selectivities of the selected analogues were examined by using the T47D alkaline phosphatase assay that was developed from human breast cancer cells with endogenous PRs.

[0285] Cotransfection Assay

[0286] The function and detailed preparation procedure of the cotransfection assays have been described previously (Pathirana, C. et al., Nonsteroidal Human Progesterone Receptor Modulators from the Marine Alga Cymopolia Barbata. Mol. Pharm. 1995, 47, 630-635). Briefly, the cotransfection assays were carried out in CV-1 cells (African green monkey kidney fibroblasts), which were transiently transfected, by the standard calcium phosphate coprecipitation procedure (Berger, T. S. et al., Interaction of Glucocorticoid Analogues with the Human Glucocorticoid Receptor. J Steroid Biochem. Mol. Bio. 1992, 41, 733-738) with the Plasmid containing receptor, MTV-LUC reporter, pRS-β-Gal, and filler DNA (Rous sarcoma virus chloramphenicol acetyltransferase). The agonist activity was determined by examining the LUC expression (normalized response) and the efficacy readout was a relative value to the maximal LUC expression produced by a reference agonist as 100%, e.g., progesterone for hPR, dihydrotestosterone (DHT) for human androgen receptor (hAR), dexamethasone for hGR, aldosterone for human mineralocorticoid receptor (hMR) and estradiol for human estrogen receptor (hER). Antagonist efficacy was determined as a function (%) of maximal inhibition of a reference agonist at EC₅₀ concentration. All the cotransfection experiments were carried out in 96-well plates by automation (Beckman Biomomek automated workstation).

[0287] Receptor Binding Assays

[0288] The preparation of receptor binding assays for hPR-A was described in literature (Pathirana, C. et al., Nonsteroidal Human Progesterone Receptor Modulators from the Marie Alga Cymopolia Barbata. Mol. Pharm. 1995, 47, 630-635.)

[0289] T47D Alkaline Phosphatase Assay

[0290] The T47D alkaline phosphatase assays were performed as described previously (Lorenzo, D. D. et. Al., Progestin Regulation of Alkaline phosphatase in the Human Breast Cancer Cell Line T47D. Cancer Res. 1991, 51, 4470).

[0291] The agonist, antagonist and binding activity assay results of selected progesterone receptor modulator compounds of the present invention and the standard reference compounds on PR are shown in Table 1 below. Efficacy is reported as the percent maximal response observed for each compound relative to the reference agonist and antagonist compounds indicated above. Also reported in Table 1 for each compound is its antagonist potency or IC₅₀ (which is the concentration (nM), required to reduce the maximal response by 50%), and its agonist potency or EC₅₀ (nM), (which is the effective concentration that produced 50% of the maximum response). Table 1 also lists the PR modulating activity in T47D cells to assess the potential tissue-selectivity comparing to marketed steroidal progestins or antiprogestins. All of the reference steroids demonstrated full agonist or antagonist activties in both cell lines; however, the 7,9-difluoro compounds of the subject invention behaved as partial agonist/antagonist activities in human breast cancer cell line despite the full agonist or antagonist activities in the CV-1 cells. TABLE 1 Agonist, antagonist and binding activity of progesterone receptor modulator compounds of present invention and the reference agonist compounds and reference antagonists compounds. hPR hPR hPR hPR Agonist Antagonist AgonistT47D Antagonists PR CV-1 Cells CV-1 Cells cells T47D Cells binding Cmpd Eff. EC₅₀ Eff. IC₅₀ Eff. EC₅₀ Eff. IC₅₀ K_(i) No. (%) (nM) (%) (nM) (%) (nM) (%) (nM) (nM) Prog. 100 0.5 na na 100 2.3 na na 3.5 MPA 88 0.4 na na 114 0.7 na na 1.4 Norethindrone 170 1.2 na na 103 0.7 na na 1.2 Levonorgestrel 216 0.1 na na 96 0.5 na na 0.4 Drospirenone 87 2.2 na na 117 6.0 na na 12 3- 190 0.1 na na 94 0.2 na na 0.3 ketodesogestrel RU486 na na 94 0.6 na na 94 3.7 1.1 ZK299 na na 99 1.6 na na 86 2.8 18 10 153 4.9 na na 54 30 49 97 6.8 14 103 7.4 na na 58 49 44 116 6.0 15 191 3.8 na na 56 19 52 711 9.7 17 169 2.9 na na 62 12 42 389 9.5 18 142 1.3 na na 57 17 58 55 3.9 19 212 1.4 na na 65 8.7 35 360 8.5 20 147 2.8 na na 63 6.6 59 170 2.9 24 52 9.4 na na 72 79 26 830 58 26 159 0.6 na na 63 7.5 46 610 9.0 29 191 2.3 na na 62 8.7 40 170 7.0 30 186 5.3 na na 66 33 44 840 4.5 31 171 2.7 na na 66 14 39 610 7.9 32 na na 76 75 36 315 35 250 37 33 85 3.5 na na 62 35 na na 2.7 34 114 1.2 na na 60 34 47 565 2.5 37 89 1.24 na na 50 130 56 150 2.2 38 110 1.2 na na 54 6.2 nt nt 2.0 39 26 28 62 24 na na 29 4100 nt 41 146 1.87 na na 54 42 50 135 2.8 45 na na 79 42 77 195 na na 18 63 154 2.3 na na 61 20 49 490 6.5 74 89 0.7 na na 58 4.6 40 53 3.5

[0292] The receptor-selectivity profile of selected analogues was examined in the cotransfection assays with different steroid hormone receptors in comparison with the steroidal reference compounds and Table 2 lists the receptor-selectivity potency ratio of selected 7,9-difluoro analogues and PR modulating steroids. In general, the nonsteroidal analogues demonstrated more selectivity towards hPR than the steroids. TABLE 2 Progesterone receptor-selectivity of selective PR modulator compounds of present invention and the reference steroidal progestins. hAR EC₅₀ hGR EC₅₀ hMR EC₅₀ hER EC₅₀ or IC₅₀/ or IC₅₀/ or IC₅₀/ or IC₅₀/ Cmpd hPR EC₅₀ hPR EC₅₀ hPR EC₅₀ hPR EC₅₀ Prog 23 >1000 25 >1000 MPA 41 67 >1000 >1000 Norethindrone 33 34 >1000 9 Levonorgestrel >1000 142 >1000 >1000 3- >1000 896 >1000 >1000 ketodesogestrel 10 320 290 >1000 >1000 14 54 365 >1000 >1000 15 2 30 >1000 >1000 17 622 66 >1000 >1000 18 170 77 >1000 >1000 19 >1000 432 >1000 >1000 20 8 27 >1000 >1000 26 742 342 >1000 >1000 29 6 83 >1000 >1000 30 377 19 >1000 >1000 31 517 59 >1000 >1000 33 37 10 >1000 >1000 34 8.5 >1000 >1000 >1000 37 558 54 >1000 >1000 41 252 105 905 >1000 63 136 8.8 >1000 685 74 100 >1000 >1000 >1000

EXAMPLE 69

[0293] The 7,9-difluoro substituents at the D-ring of formulae I and II of the present invention are generally superior to any other substituents in modulating PR activities, which is unexpected and surprising, in view of U.S. Pat. No. 5,693,646 and U.S. Pat. No. 5,696,127. The superiority of the 7,9-difluoro analogue compounds of the present invention was demonstrated utilizing the hPR cotransfection assay according to the following illustrative Examples. The EC₅₀ comparison between the new 7,9-difluoro compounds and analogues with substitution patterns different from 7,9-difluoro (disclosed in U.S. Pat. No. 5,693,646 and U.S. Pat. No. 5,696,127) are tabulated in Tables 3 and 4. TABLE 3 hPR agonist potencies (EC₅₀ in nM) of selected 7,9-difluoro compounds of present invention (Formula I) and analogues with other D-ring substitution patterns in the cotransfection assay.

X → 7,9-diF H 9-F 9-OMe 9-Cl 9-Me 8-F R⁸ # EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ Ph 33 3.5  203^(a)  7.4^(b) —^(c) 6.9^(b) — — 3-F-Ph 40 6.66   9^(a) — — 3.7^(b) — — 3-Cl-Ph 41 1.87  18^(b)  2.8^(b) — 3.6^(b)  4.85 — 4-Cl-Ph 43 5.1  15^(b)  8.1^(b)  3.1^(b) 9^(b) —  10^(b) 3-Br-Ph 42 3.65   8^(b) — — — — — 4-Br-Ph 36 4.96  14^(b) — — 5.2^(b) — — 3-Me-Ph 34 1.2  145  5.0^(b) 11 7.1^(b) 44 — 3-CF₃-Ph 56 1.6  13^(a) 10^(b) — 7.4 — — 4-Cl-3-Me-Ph 37 1.24  14^(b)  2.7^(b) — 9.4  7.45 — Benzodioxol- 35 3.85  48 — — — — — 5-yl Me 44 1.4 2067 13 — 3 — — Et 46 6.93 —  9 — — — — Allyl 55 3.6  839  7.5 — — — — Bu 52 15  16^(a) 16^(a)  9 7 16 5285

[0294] TABLE 4 hPR agonist potencies (EC₅₀ in nM) of selected 7,9-difluoro compounds of present invention (Formula II) and analogues with other D-ring substitution patterns in the cotransfection assay.

X → 7,9-diF H 9-F 8-OH 9-OH 8-OMe 9-OMe 7-Cl 9-Cl 9-Me 8-F 8,9-diF R⁹ # EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ Phenyl 10 4.9 33^(a)  5.25 —^(c) 54.4 5.5 67 6.2  6.24 — 187 — 2-F-Ph 12 2.55 29^(b)  7.3 — — 45 — — 26.5 — — — 3-F-Ph 15 3.8  7.6^(b)  7 —  5.75 8.6 — — 11.6 7.95 109 — 4-F-Ph 16 3.7 59.5^(b)  3.95 — — — — — — — — — 2-Cl-Ph 13 1.92 57.8^(b) 12 — — >1000 — — — — — — 2,5-diF-Ph 17 2.9 14.7^(b)  3 10 10 — — — 25 — — — 2-Me-3-F-Ph 21 8.2 —  8.4 — — — — — — — — — 2-Me-5-F-Ph 19 1.4  2.6  2.1 — — — — —  2.1 — —  3.95 2-MeO-5-F-Ph 26 0.6 —  0.9 — 11.5 — — — — — — — 2-MeO-Ph 18 1.3 —  0.93 — — 24.0 — — — — — — 2-Me-Ph 81 1.66  5.7^(b)  4^(a) —  9.3 3.5 67.5 —  8.5 —  13 13 4-pyridinyl 14 7.4 —  5.8 — — 36 — — — — — — 3-Me-4-pyridinyl 20 2.8 —  2.0 — — 24 — — — — — — 2-Thienyl 31 2.7 — 18 — — — — — — — — —

EXAMPLE 70

[0295] The 7,9-difluoro substituents at the D-ring of formulae I and II of the present invention are generally superior to any other substituents in tissue-selectivity, which is unexpected and surprising, in view of U.S. Pat. No. 5,693,646 and U.S. Pat. No. 5,696,127. The superiority of the 7,9-difluoro analogue compounds of the present invention was further characterized utilizing a multi-endpoint adult rat model according to the following illustrative Examples. In this assay, advantage is taken of the fact that in the uterus, estrogens induce a proliferation and increase in the epithelial cell height and uterine wet weight, which can be antagonized by progestins. In the breast, estrogens induce a proliferation of the ductal network while progestins stimulate the growth of the lobular-alveolar end buds, which grow from the distal end of the ducts. The assay is carried out in ovariectomized female rats by treating them for three days with estrone or estrone plus varying doses of a progestin; in this case MPA was used. Proliferating cells or inhibition of proliferating cells were quantitated either by measurements of cell height in sectioned and stained tissue samples or, in the case of the breast, immuno-histochemically labeled Brdu incorporated nuclei. The tissue-selectivity comparison between the new 7,9-difluoro compounds and analogues with substitution patterns different from 7,9-difluoro (disclosed in U.S. Pat. No. 5,693,646 and U.S. Pat. No. 5,696,127) are tabulated in Tables 5 and 6. The uterus/breast tissue-selectivity is presented as the ratio of relative efficacy to MPA in uterus verse in breast tissue at the same highest dose tested. TABLE 5 The uterus/breast tissue-selectivity of selected 7,9-difluoro compounds of present invention (Formula I) and analogues with other D-ring substitution patterns in an adult rat model.

X → 7,9-diF H 9-F R⁸ Compd # selectivity selectivity selectivity Ph 33 —^(a) 0.78 — n-butyl 52 — — 2.0 2-benzo-thiophene 64 2.8 — — 4-Cl-3-Me-Ph 38 2.8 — — 1-propynyl 75 4.2 — — 4-Cl-Ph 43 — 1.5  — 3-CF₃-Ph 56 — 3.5  —

[0296] TABLE 6 The uterus/breast tissue-selectivity of selected 7,9-difluoro compounds of present invention (Formula II) and analogues with other D-ring substitution patterns in an adult rat model.

X → 7,9-diF H 9-F R⁸ Compd # selectivity selectivity selectivity 2,5-diF-Ph 17 2.7 —^(a) — 3-F-Ph 15 — 0.69 2.2 2-thienyl 31 3.5 — — 2-Me-5-F-Ph 19 3.5 — — 2-Me-Ph 81 — — 2.3

EXAMPLE 71

[0297] The 7,9-difluoro substituents at the D-ring of formulae I and II of the present invention are generally superior to any other substituents in PR agonist activity in vivo, which is unexpected and surprising, in view of U.S. Pat. No. 5,693,646 and U.S. Pat. No. 5,696,127. The superiority of the 7,9-difluoro analogue compounds of the present invention was further characterized utilizing the McPhail rabbit model according to the following illustrative Examples. The Clauberg or McPhail assay is a classic assay utilizing rabbits to measure progestational activity. The reason rabbit is used is because the results observed in rabbit have proved to be a good indicator and predictor of activity in the human. In this assay, immature rabbits are treated initially with estradiol, which induces growth in the uterus. This is followed by a progestin, which causes a large change in the glandular content of the uterus. It is this change in the glandular component which is a measure of the progestational activity of a progestin. The measurement of these glandular changes is carried out histologically using stained sections of the uterus. The in vivo comparison between the new 7,9-difluoro compounds and analogues with substitution patterns different from 7,9-difluoro (U.S. Pat. No. 5,693,646 and U.S. Pat. No. 5,696,127) is tabulated in Tables 7 and 8. The in vivo potency of the progestins is presented as the minimum active dose (MAD). TABLE 7 The potency (MAD in mg/kg) of selected 7,9-difluoro compounds of present invention (Formula I) and analogues with other D-ring substitution patterns in the McPhail assay.

X → 7,9-diF 7-F 9-F 9-Me R⁸ Compd # MAD MAD MAD MAD 3-F-Ph 40 —^(a) — — >2 3-Me-Ph 34 1.0 — — — 2-benzo-thiophene 64 0.25 — — — 4-Cl-3-Me-Ph 38 0.25 0.5 1.0 — 1-propynyl 75 <0.5 — — — 2-propynyl 71 <0.5 — — — 3-Cl-Ph 41 0.75 — — —

[0298] TABLE 8 The potency (MAD in mg/kg) of selected 7,9-difluoro compounds of present invention (Formula II) and analogues with other D-ring substitution patterns in the McPhail assay.

X → 7,9-diF 7-F 9-F R⁸ Compd # MAD MAD MAD 2,5-diF-Ph 17 0.25 0.5 —^(a) 2-F-Ph 12 0.5 — — 3-F-Ph 15 0.18 — — 2-MeO-Ph 18 2.0 — — 2-Me-5-F-Ph 19 0.1 1.0 — 2-MeO-5-F-Ph 26 2.0 — — 2-Me-Ph 81 — — 1.2 3-Me-pyridine-4- 20 0.25 — —

[0299] Pharmacological and Other Applications

[0300] The following Example provides illustrative pharmaceutical composition formulations:

EXAMPLE 72

[0301] Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) COMPOUND 10  10 Starch, dried 200 Magnesium stearate  10 Total 220 mg

[0302] The above ingredients are mixed and filled into hard gelatin capsules in 220 mg quantities.

[0303] A tablet is prepared using the ingredients below: Quantity (mg/tablet) COMPOUND 10  10 Cellulose, microcrystalline 200 Silicon dioxide, fumed  10 Stearic acid  10 Total 230 mg

[0304] The components are blended and compressed to form tablets each weighing 230 mg.

[0305] Tablets, each containing 10 mg of active ingredient, are made as follows: Quantity (mg/tablet) COMPOUND 10   10 Starch   45 Cellulose, microcrystalline   35 Polyvinylpyrrolidone (PVP)   4 (as 10% solution in water) Sodium carboxymethyl starch (SCMS)  4.5 Magnesium stearate  0.5 Talc  1.0 Total  100 mg

[0306] The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of PVP is mixed with the resultant powders, which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50° C. and passed through a No. 18 mesh U.S. sieve. The SCMS, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

[0307] Suppositories, each containing 225 mg of active ingredient, may be made as follows: Quantity (mg/suppository) COMPOUND 10   20 Saturated fatty acid glycerides 2,000 Total 2,020 mg

[0308] The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of normal 2 g capacity and allowed to cool.

[0309] An intravenous formulation may be prepared as follows: Quantity COMPOUND 10  10 mg isotonic saline 1000 mL glycerol  100 mL

[0310] The compound is dissolved in the glycerol and then the solution is slowly diluted with isotonic saline. The solution of the above ingredients is then administered intravenously at a rate of 1 mL per minute to a patient.

[0311] The present invention includes any combination of the various species and subgeneric groupings falling within the generic disclosure. This invention therefore includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0312] The scope of the invention is not limited by the description of the examples. Modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention.

[0313] Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific examples which have been presented by way of example. 

What is claimed is:
 1. A compound of the formula:

wherein: R⁸ is selected from the group of C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ heteroalkenyl, C₂-C₁₂ haloalkenyl, C₂-C₁₂ alkynyl, C₂-C₁₂ heteroalkynyl, C₂-C₁₂ haloalkynyl, aryl and heteroaryl, optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹; R⁹ is selected from the group of hydrogen, F, Cl, Br, I, CN, C₁-C₈ alkyl, C₁-C8 heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkenyl or cycloalkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ haloalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₂-C₈ haloalkynyl, aryl and heteroaryl, optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰R¹¹; R¹⁰ and R¹¹ each independently is hydrogen, or C₁-C₄ alkyl; or a pharmaceutically acceptable salt or prodrug thereof.
 2. A compound according to claim 1, wherein R⁸ is selected from the group of C₁-C₈ alkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ haloalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₂-C₈ haloalkynyl, aryl and heteroaryl, optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹.
 3. A compound according to claim 2, wherein R is selected from the group of C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄ heteroalkenyl, C₂-C₄ haloalkenyl, C₂-C₄ alkynyl, C₂-C₄ heteroalkynyl, and C₂-C₄ haloalkynyl.
 4. A compound according to claim 2, wherein R⁸ is selected from the group of aryl and heteroaryl radicals, wherein said aryl and heteroaryl radicals are optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, CN, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹.
 5. A compound according to claim 2, wherein R⁸ is selected from the group of

R¹ and R² each independently is selected from the group of hydrogen, F, Cl, Br and C₁-C₄ alkyl; R³ through R⁵ each independently is selected from group of hydrogen, F, Cl, and C₁-C₄ alkyl; n is 0 or 1; and Y is selected from the group of O, S, and NR¹⁰.
 6. A compound according to claim 1, wherein R⁹ is selected from the group of hydrogen, F, Cl, Br, CN, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or cycloalkenyl, C₂-C₆ heteroalkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ heteroalkynyl, C₂-C₆ haloalkynyl, aryl and heteroaryl optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹.
 7. A compound according to claim 6, wherein R⁹ is selected from the group of hydrogen, Br, C₁, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄ heteroalkenyl, C₂-C₄ haloalkenyl, C₂-C₄ alkynyl and C₂-C₄ heteroalkynyl, C₂-C₄ haloalkynyl.
 8. A compound according to claim 6, wherein R⁹ is selected from the group of aryl and heteroaryl radicals, wherein said aryl and heteroaryl radicals are optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, CN, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹.
 9. A compound according to claim 6, wherein R⁹ is selected from the group of

R⁶ is selected from the group of hydrogen, F, Cl, Br, C₁-C₄ alkyl, OR¹⁰, SR¹⁰, and NR¹⁰R¹¹; R⁷ is hydrogen, F, or Cl; R¹⁰ and R¹¹ each independently is hydrogen, or C₁-C₄ alkyl; X is CH or N; and Y is selected from the group of O, S, and NR¹⁰.
 10. A compound according to claim 9, wherein R⁹ is

R⁶ is selected from the group of hydrogen, F, Cl, C₁-C₄ alkyl, OMe, OEt, NHMe, and NMe₂; R⁷ is hydrogen, F, or Cl; and X is CH or N.
 11. A compound according to claim 9, where R⁶ is selected from the group of F, Me, Et, OMe, OEt, SMe, and NMe₂.
 12. A compound according to claim 1, wherein said compound is selected from the group of: 7,9-difluoro-5(Z)-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 10); 7,9-difluoro-5(Z)-(2-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 12); 7,9-difluoro-5(Z)-(2-chlorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 13); 7,9-difluoro-5(Z)-(4-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 14); 7,9-difluoro-5(Z)-(3-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 15); 7,9-difluoro-5(Z)-(4-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 16); 7,9-difluoro-5(Z)-(2,5-difluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 17); 7,9-difluoro-5(Z)-(2-methoxybenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 18); 7,9-difluoro-5(Z)-(2-methyl-5-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 19); 7,9-difluoro-5(Z)-(3-methyl-4-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 20); 7,9-difluoro-5(Z)-(2-methyl-3-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 21); 7,9-difluoro-5(Z)-(3-methyl-2-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 22); 7,9-difluoro-5(Z)-(2,3-dimethylbenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 23); 7,9-difluoro-5(Z)-cyanomethylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 24); 7,9-difluoro-5 (Z)-hexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 25); 7,9-difluoro-5(Z)-(2-methoxy-5-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 26); 7,9-difluoro-5(Z)-(2,4,5-trifluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 27); 7,9-difluoro-5-methylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 28); 7,9-difluoro-5(Z)-bromomethylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 29); 7,9-difluoro-5(Z)-(3-thienylmethylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 30); 7,9-difluoro-5(Z)-(2-thienylmethylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 31); (±)-7,9-difluoro-5-methoxy-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 32); (±)-7,9-difluoro-5-phenyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 33); (±)-7,9-difluoro-5-(3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 34); (±)-7,9-difluoro-5-(1,3-benzodioxol-5-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 35); (±)-7,9-difluoro-5-(4-bromophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 36); (±)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 37); (−)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 38); (+)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 39); (±)-7,9-difluoro-5-(3-fluorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 40); (±)-7,9-difluoro-5-(3-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 41); (±)-7,9-difluoro-5-(3-bromophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 42); (±)-7,9-difluoro-5-(4-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 43); (±)-7,9-difluoro-1,2-dihydro-2,2,4,5-tetramethyl-5H-chromeno[3,4-f]quinoline (Compound 44); (±)-7,9-difluoro-5-(2-oxo-2-phenylethyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 45); (±)-7,9-difluoro-5-ethyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 46); (±)-7,9-difluoro-5-ethenyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 47); (±)-7,9-difluoro-5-(2-oxo-3-butenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 48); (±)-7,9-difluoro-1,2-dihydro-α,α,2,2,4-pentamethyl-5H-chromeno[3,4-f]quinoline-5-ethanoate (Compound 49); (±)-7,9-difluoro-5-ethynyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 50); (±)-7,9-difluoro-5-cyano-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 51); (±)-7,9-difluoro-5-butyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 52); (±)-7,9-difluoro-5-(2-thienyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 53); (±)-7,9-difluoro-5-(2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 54); (±)-7,9-difluoro-5-allyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 55); (±)-7,9-difluoro-5-[3-(trifluoromethyl)phenyl]-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 56); Ethyl (±)-7,9-difluoro-1,2-dihydro-α-methylene-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline-5-propanoate (Compound 57); (±)-7,9-difluoro-1,2-dihydro-β-methylene-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline-5-propanol (Compound 58); (±)-7,9-difluoro-1,2-dihydro-13-methylene-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline-5-propanol acetate(Compound 59); (±)-7,9-difluoro-5-(1-methylethenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 60); (±)-7,9-difluoro-5-(N-methyl-2-pyrrolyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 61); (±)-7,9-difluoro-5-phenylethynyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 62); (±)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 63); (−)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 64); (+)-7,9-difluoro-5-(benzo[b]thie-2yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 65); (±)-7,9-difluoro-5-(5-methyl-2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 66); (±)-7,9-difluoro-5-(2-benzo[b] furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 67); (±)-7,9-difluoro-5-[4-(dimethylamino)phenyl]-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 68); (±)-7,9-difluoro-5-(5-methyl-2-thienyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 69); (±)-7,9-difluoro-5-(5-methoxy-2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 70); (±)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 71); (−)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 72); (+)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 73); (±)-7,9-difluoro-5-(1-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 74); (−)-7,9-difluoro-5-(1-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 75); (+)-7,9-difluoro-5-(1-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 76); (±)-7,9-difluoro-5-(4,5-dimethyl-2-furyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 77); (±)-7,9-difluoro-5-(2-methyl-1-propenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 78); (±)-7,9-difluoro-5-(3,4-dimethyl-2-thienyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 79); (±)-7,9-difluoro-5-(3-(3-bromophenyl)phenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 80); and 7,9-difluoro-5-(2-methylbenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 81).
 13. A compound according to claim 1, wherein said compound is selected from the group of: 7,9-difluoro-5(Z)-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 10); 7,9-difluoro-5(Z)-(2-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 12); 7,9-difluoro-5(Z)-(3-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 15); 7,9-difluoro-5(Z)-(2,5-difluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 17); 7,9-difluoro-5 (Z)-(2-methoxybenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 18); 7,9-difluoro-5(Z)-(2-methyl-5-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 19); 7,9-difluoro-5(Z)-(3-methyl-4-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 20); 7,9-difluoro-5(Z)-(2-methoxy-5-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 26); 7,9-difluoro-5(Z)-(3-thienylmethylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 30); 7,9-difluoro-5(Z)-(2-thienylmethylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 31); (±)-7,9-difluoro-5-(3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 34); (−)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 38); (+)-7,9-difluoro-5-(3-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 41); (±)-7,9-difluoro-1,2-dihydro-2,2,4,5-tetramethyl-5H-chromeno[3,4-f]quinoline (Compound 44); (±)-7,9-difluoro-5-allyl-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 55); (±)-7,9-difluoro-5-(3-trifluoromethylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 56); (±)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 63); (−)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 64); (+)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 65); (−)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 72); (−)-7,9-difluoro-5-(1-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 75); and 7,9-difluoro-5-(2-methylbenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 81).
 14. A compound according to claim 1, wherein said compound is selected from the group of: 7,9-difluoro-5(Z)-(2,5-difluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 17); 7,9-difluoro-5(Z)-(2-methyl-5-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 19); 7,9-difluoro-5 (Z)-(3-methyl-4-picolylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 20); 7,9-difluoro-5(Z)-(2-methoxy-5-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 26); (−)-7,9-difluoro-5-(4-chloro-3-methylphenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 38); (±)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 63); (−)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 64); (±)-7,9-difluoro-5-(benzo[b]thien-2-yl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 65); and (−)-7,9-difluoro-5-(2-propynyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 72).
 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula:

wherein: R⁸ is selected from the group of C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ heteroalkenyl, C₂-C₁₂ haloalkenyl, C₂-C₁₂ alkynyl, C₂-C₁₂ heteroalkynyl, C₂-C₁₂ haloalkynyl, aryl and heteroaryl optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹; R⁹ is selected from the group of hydrogen, F, Cl, Br, I, CN, C₁-C₈ alkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkenyl or cycloalkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ haloalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₂-C₈ haloalkynyl, aryl and heteroaryl optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR⁰R¹¹¹; R¹⁰ and R¹¹ each independently is hydrogen, or C₁-C₄ alkyl;  or a pharmaceutically acceptable salt or prodrug thereof.
 16. A pharmaceutical composition according to claim 15, wherein R⁸ is selected from the group of C₁-C₈ alkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ haloalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₂-C₈ haloalkynyl, aryl and heteroaryl, optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹.
 17. A pharmaceutical composition according to claim 16, wherein R⁸ is selected from the group of C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄ heteroalkenyl, C₂-C₄ haloalkenyl, and C₂-C₄ alkynyl, C₂-C₄ heteroalkynyl and C₂-C₄ haloalkynyl.
 18. A pharmaceutical composition according to claim 16, wherein R⁸ is selected from the group of aryl and heteroaryl radicals, wherein said aryl and heteroaryl radicals are optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, CN, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, OR¹⁰, SR¹⁰, and NR¹⁰R¹¹.
 19. A pharmaceutical composition according to claim 16, wherein R⁸ is selected from the group of

R¹ and R² each independently is selected from the group of hydrogen, F, Cl, Br and C₁-C₄ alkyl; R³ through R⁵ each independently is selected from the group of hydrogen, F, Cl, and C₁₋₄ alkyl; n is 0 or 1; and Y is selected from the group of O, S, and NR¹⁰.
 20. A pharmaceutical composition according to claim 15, wherein R⁹ is selected from the group of hydrogen, F, Cl, Br, CN, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or cycloalkenyl, C₂-C₆ heteroalkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ heteroalkynyl, C₂-C₆ haloalkynyl, aryl and heteroaryl, optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰R¹¹.
 21. A pharmaceutical composition according to claim 20, wherein R⁹ is selected from the group of hydrogen, Br, C₁, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄ heteroalkenyl, C₂-C₄ haloalkenyl, C₂-C₄ alkynyl, C₂-C₄ heteroalkynyl, and C₂-C₄ haloalkynyl.
 22. A pharmaceutical composition according to claim 20, wherein R⁹ is selected from the group of aryl and heteroaryl radicals, wherein said aryl and heteroaryl radicals are optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, CN, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹.
 23. A pharmaceutical composition according to claim 22, wherein R⁹ is selected from the group of

R⁶ is selected from the group of hydrogen, F, Cl, Br, C₁-C₄ alkyl, OR¹⁰, SR¹⁰, and NR¹⁰R¹¹; R⁷ is hydrogen, F, or Cl; R¹⁰ and R¹¹ each independently is hydrogen, or C₁-C₄ alkyl; X is CH or N; and Y is selected from group of O, S, and NR¹⁰.
 24. A pharmaceutical composition according to claim 23, wherein R⁹ is

R⁶ is selected from the group of hydrogen, F, Cl, C₁-C₄ alkyl, OMe, OEt, NHMe, and NMe₂; and R⁷ is hydrogen, F, or Cl.
 25. A pharmaceutical composition according to claim 23, where R⁶ is selected from the group of F, Me, Et, OMe, OEt, SMe, and NMe₂.
 26. A method of treating an individual having a condition mediated by a progesterone receptor comprising administering to said individual a pharmaceutically effective amount of a compound according to any one of claims 1 to
 14. 27. A method according to claim 26, wherein said compound is represented by formula (I):

wherein: R⁸ is selected from the group of C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ heteroalkenyl, C₂-C₁₂ haloalkenyl, C₂-C₁₂ alkynyl, C₂-C₁₂ heteroalkynyl, C₂-C₁₂ haloalkynyl, aryl and heteroaryl, optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹; or a pharmaceutically acceptable salt or prodrug thereof.
 28. A method according to claim 26, wherein said compound is represented by formula (II):

wherein: R⁹ is selected from the group of hydrogen, F, Cl, Br, I, CN, C₁-C₈ alkyl, C₁-C₈ heteroalkyl, C₁-C₈ haloalkyl, C₂-C₈ alkenyl or cycloalkenyl, C₂-C₈ heteroalkenyl, C₂-C₈ haloalkenyl, C₂-C₈ alkynyl, C₂-C₈ heteroalkynyl, C₂-C₈ haloalkynyl, aryl and heteroaryl, optionally substituted with one or more substituents independently selected from the group of hydrogen, C₁-C₄ alkyl, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CF₃, C(O)CH₃, CO₂CH₃, C(O)NH₂, OR¹⁰, SR¹⁰, and NR¹⁰OR¹¹;  or a pharmaceutically acceptable salt or prodrug thereof.
 29. A method according to claim 26, wherein said condition is selected from the group of dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas (uterine fibroids), hot flushes, mood disorders, meningiomas, hormone-dependent cancers, and female osteoporosis.
 30. A method of modulating fertility in an individual comprising administering to said individual a pharmaceutically effective amount of a compound according to any one of claims 1 to
 25. 31. A method of providing contraception in an individual comprising administering to said individual a pharmaceutically effective amount of a compound according to any one of claims 1 to
 25. 32. A method according to claim 26, wherein said condition is alleviated with female hormone replacement therapy.
 33. A method of modulating a progesterone receptor in an individual comprising administering a progesterone modulating effective amount of a compound according to any one of claims 1 to
 25. 34. A method according to claim 33, wherein said modulation is activation.
 35. A method according to claim 34, wherein said compound provides at least 50% maximal activation of the progesterone receptor at a blood plasma concentration of less than 100 nM.
 36. A method according to claim 34, wherein said compound provides at least 50% maximal activation of the progesterone receptor at a blood plasma concentration of less than 50 nM.
 37. A method according to claim 34, wherein said compound provides at least 50% maximal activation of the progesterone receptor at a blood plasma concentration of less than 20 nM.
 38. A method according to claim 34, wherein said compound provides at least 50% maximal activation of the progesterone receptor at a blood plasma concentration of less than 10 nM.
 39. A method of treating an individual having cancer comprising administering to said individual a pharmaceutically effective amount of a compound according to any one of claims 1 to
 25. 40. A method of determining the presence of a progesterone receptor in a cell or cell extract comprising (a) labeling a compound according to any one of claims 1 to 25; (b) contracting the cell or cell extract with said labeled compound; and (c) testing the contracted cell or cell extract to determine the presence of progesterone receptor. 